Tyk2 pseudokinase ligands

ABSTRACT

Described herein are TYK2 pseudokinase ligands and methods of utilizing TYK2 pseudokinase ligands in the treatment of diseases, disorders or conditions. Also described herein are pharmaceutical compositions containing such compounds.

CROSS-REFERENCE

This application is a continuation of U.S. application Ser. No.17/441,788, filed Sep. 22, 2021, which is a National Phase applicationof PCT/US2020/024746, filed Mar. 25, 2020, which claims benefit of U.S.Provisional Application No. 62/824,144, filed on Mar. 26, 2019, each ofwhich is herein incorporated by reference in its entirety.

BACKGROUND OF THE INVENTION

Janus kinase (JAK) is a family of intracellular, non-receptor tyrosinekinases that transduce cytokine-mediated signals via the JAK-STATpathway. The four JAK family members are Janus kinase 1 (JAK1), Januskinase 2 (JAK2), Janus kinase 3 (JAK3), and Tyrosine kinase 2 (TYK2) andhave been shown to be key components of cytokine-mediated effects.Unlike JAK1 deficient mice, TYK2 deficient mice are viable and the TYK2deficiency has been shown to be protective in various models ofautoimmunity.

SUMMARY OF THE INVENTION

In one aspect, provided herein are compounds of Formula (I) or Formula(II):

wherein:

-   -   is C₃-C₆cycloalkyl, C₆-C₁₀aryl, C₂-C₉heterocycloalkyl, or        C₂-C₉heteroaryl, wherein C₃-C₆cycloalkyl, C₆-C₁₀aryl,        C₂-C₉heterocycloalkyl, or C₂-C₉heteroaryl is optionally        substituted with 1, 2, 3, or 4 R₇;    -   X is —O—, —C(R₉)(R₁₀)—, —C(R₉)(R₁₀)—O—, —O—C(R₉)(R₁₀), —C(O)—,        —C(O)N(R₃)—, —N(R₃)C(O)—, or —N(R₁₇)—;    -   L₁ is —C(O)N(R₃)—, —N(R₃)C(O)—, —C(R₉)(R₁₀)—O—, or        —O—C(R₉)(R₁₀)—;    -   L₂ is —N(R₆)—, —N(R₆)CH₂—, or —CH₂N(R₆)—;    -   each R₁ is independently selected from hydrogen, deuterium,        C₁-C₆alkyl, and C₁-C₆deuteroalkyl;    -   each R₂ is independently selected from hydrogen, deuterium,        C₁-C₆alkyl, and C₁-C₆deuteroalkyl; or R₁ and R₂ are combined to        form a 3-, 4-, 5-, or 6-membered cycloalkyl ring or a 4-, 5-, or        6-membered heterocycloalkyl ring;    -   each R₃ is independently hydrogen or C₁-C₆alkyl; or R₂ and R₃        together with the atoms to which they are attached are combined        to form a 5- or 6-membered heterocycloalkyl ring optionally        substituted 1, 2, or 3 with groups selected from halogen, —OH,        C₁-C₆alkyl, and —C₁-C₆alkyl-OH;    -   R₄ is selected from hydrogen, deuterium, C₁-C₆alkyl,        C₁-C₆deuteroalkyl, C₁-C₆heteroalkyl, C₃-C₆cycloalkyl, and        C₂-C₉heterocycloalkyl;    -   R₅ is selected from hydrogen, deuterium, C₁-C₆alkyl,        C₁-C₆deuteroalkyl, C₁-C₆heteroalkyl, C₃-C₆cycloalkyl, and        C₂-C₉heterocycloalkyl;    -   R₁₃ is hydrogen, deuterium, C₁-C₆alkyl, or C₁-C₆deuteroalkyl; or        R₅ and R₁₃ together with the atoms to which they are attached        are combined to form a 5- or 6-membered heterocycloalkyl ring or        a 5- or 6-membered heteroaryl ring, wherein the 5- or 6-membered        heterocycloalkyl ring or 5- or 6-membered heteroaryl ring is        optionally substituted with 1, 2, or 3 groups selected from        halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, and        C₁-C₆haloalkoxy;    -   R₆ is hydrogen or C₁-C₆alkyl;    -   each R₇ is independently selected from deuterium, halogen,        C₁-C₆alkyl, C₁-C₆deuteroalkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy,        C₁-C₆heteroalkyl, oxo, —OR₁₁, —N(R₁₁)₂, —CN, —C(═O)R₁₂,        —C(═O)OR₁₁, —C(═O)N(R₁₁)₂, —NR₁₁C(═O)R₁₂, —NR₁₁S(═O)₂R₁₂,        —S(═O)₂R₁₂, and —S(═O)₂N(R₁₁)₂;    -   each R₉ and each R₁₀ are independently selected from hydrogen,        deuterium, C₁-C₆alkyl, and C₁-C₆deuteroalkyl;    -   each R₁₁ is independently selected from hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆heteroalkyl, and phenyl, wherein phenyl is        optionally substituted with 1, 2, or 3 groups selected from        halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy,        C₁-C₆haloalkoxy, C₂-C₉heterocycloalkyl, C₂-C₉heteroaryl, —OR₁₄,        —N(R₁₄)₂, —C(═O)OR₁₄, and —C(═O)N(R₁₄)₂;    -   each R₁₂ is independently selected from C₁-C₆alkyl and        C₁-C₆heteroalkyl;    -   each R₁₄ is independently selected from hydrogen, C₁-C₆alkyl,        and C₁-C₆haloalkyl;    -   R₁₇ is hydrogen or C₁-C₆alkyl;    -   R₁₈ is hydrogen, deuterium, halogen, C₁-C₆alkyl, or        C₁-C₆deuteroalkyl; and    -   n is 1, 2, 3, or 4;    -   or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof:

In some embodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt or solvate thereof:

In some embodiments is a compound of Formula (I) or (II), or apharmaceutically acceptable salt or solvate thereof, wherein

is C₆-C₁₀aryl optionally substituted with 1, 2, or 3 R₇. In someembodiments is a compound of Formula (I) or (II), or a pharmaceuticallyacceptable salt or solvate thereof, wherein

is phenyl optionally substituted with 1, 2, or 3 R₇. In some embodimentsis a compound of Formula (I) or (II), or a pharmaceutically acceptablesalt or solvate thereof, wherein

is C₂-C₉heteroaryl optionally substituted with 1, 2, or 3 R₇. In someembodiments is a compound of Formula (I) or (II), or a pharmaceuticallyacceptable salt or solvate thereof, wherein

is C₂-C₉heteroaryl selected from oxazolyl, thiazolyl, pyrazolyl,furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, isoxazolyl,isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl,wherein oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl,imidazolyl, triazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl,pyrazinyl, and pyridazinyl are optionally substituted with 1, 2, or 3R₇. In some embodiments is a compound of Formula (I) or (II), or apharmaceutically acceptable salt or solvate thereof, wherein R₇ isselected from halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, and —CN.In some embodiments is a compound of Formula (I) or (II), or apharmaceutically acceptable salt or solvate thereof, wherein

is C₂-C₉heteroaryl selected from:

In some embodiments is a compound of Formula (I) or (II), or apharmaceutically acceptable salt or solvate thereof, wherein

is C₂-C₉heterocycloalkyl optionally substituted with 1, 2, or 3 R₇. Insome embodiments is a compound of Formula (I) or (II), or apharmaceutically acceptable salt or solvate thereof, wherein

is C₃-C₆cycloalkyl optionally substituted with 1, 2, 3, or 4 R₇. In someembodiments is a compound of Formula (I) or (II), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₇ is selected from halogen,C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, and oxo. In some embodiments isa compound of Formula (I) or (II), or a pharmaceutically acceptable saltor solvate thereof, wherein

is C₂-C₉heterocycloalkyl selected from:

In some embodiments is a compound of Formula (I) or (II), or apharmaceutically acceptable salt or solvate thereof, wherein L₁ is—C(O)N(R₃)—. In some embodiments is a compound of Formula (I) or (II),or a pharmaceutically acceptable salt or solvate thereof, wherein L₂ is—N(R₆)—.

In another aspect, provided herein are compounds of Formula (III) orFormula (IV):

wherein:

-   -   X is —O— or —C(R₉)(R₁₀)—;    -   Y is =N— or ═C(R₁₅)—;    -   Z is =N— or ═C(R₁₆)—;    -   each R₁ is independently selected from hydrogen, deuterium,        C₁-C₆alkyl, and C₁-C₆deuteroalkyl;    -   each R₂ is independently selected from hydrogen, deuterium,        C₁-C₆alkyl, and C₁-C₆deuteroalkyl;    -   R₃ is hydrogen or C₁-C₆alkyl;    -   R₄ is selected from hydrogen, deuterium, C₁-C₆alkyl,        C₁-C₆deuteroalkyl, C₁-C₆heteroalkyl, C₃-C₆cycloalkyl, and        C₂-C₉heterocycloalkyl;    -   R₅ is selected from hydrogen, deuterium, C₁-C₆alkyl,        C₁-C₆deuteroalkyl, C₁-C₆heteroalkyl, C₃-C₆cycloalkyl, and        C₂-C₉heterocycloalkyl;    -   R₁₃ is hydrogen, deuterium, C₁-C₆alkyl, or C₁-C₆deuteroalkyl; or        R₅ and R₁₃ together with the atoms to which they are attached        are combined to form a 5- or 6-membered heterocycloalkyl ring or        a 5- or 6-membered heteroaryl ring, wherein the 5- or 6-membered        heterocycloalkyl ring or 5- or 6-membered heteroaryl ring is        optionally substituted with 1, 2, or 3 groups selected from        halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, and        C₁-C₆haloalkoxy;    -   R₆ is hydrogen or C₁-C₆alkyl;    -   R₇ and R₈ are independently selected from hydrogen, deuterium,        halogen, C₁-C₆alkyl, C₁-C₆deuteroalkyl, —C₁-C₆alkyl-OH,        C₁-C₆haloalkyl, C₁-C₆alkoxy, C₃-C₆cycloalkyl,        C₂-C₉heterocycloalkyl, C₂-C₉heteroaryl, C₆-C₁₀aryl, —OR₁₁,        —N(R₁₁)₂, —CN, —C(═O)R₁₂, —C(═O)OR₁₁, —C(═O)N(R₁₁)₂,        —NR₁₁C(═O)R₁₂, —NR₁₁S(═O)₂R₁₂, —S(═O)₂R₁₂, and —S(═O)₂N(R₁₁)₂,        wherein C₃-C₆cycloalkyl, C₂-C₉heterocycloalkyl, C₂-C₉heteroaryl,        or C₆-C₁₀aryl are optionally substituted with 1, 2, or 3 groups        selected from halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy,        and C₁-C₆haloalkoxy;    -   R₉ and R₁₀ are independently selected from hydrogen, deuterium,        C₁-C₆alkyl, and C₁-C₆deuteroalkyl;    -   each R₁ is independently selected from hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆heteroalkyl, and phenyl, wherein phenyl is        optionally substituted with 1, 2, or 3 groups selected from        halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy,        C₁-C₆haloalkoxy, C₂-C₉heterocycloalkyl, C₂-C₉heteroaryl, —OR₁₄,        —N(R₁₄)₂, —C(═O)OR₁₄, and —C(═O)N(R₁₄)₂;    -   each R₁₂ is independently selected from C₁-C₆alkyl and        C₁-C₆heteroalkyl;    -   each R₁₄ is independently selected from hydrogen, C₁-C₆alkyl,        and C₁-C₆haloalkyl;    -   R₁₅ and R₁₆ are independently selected from hydrogen, deuterium,        halogen, C₁-C₆alkyl, C₁-C₆deuteroalkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆heteroalkyl, —OR₁₁, —N(R₁₁)₂, —CN, —C(═O)R₁₂,        —C(═O)OR₁₁, —C(═O)N(R₁₁)₂, —NR₁₁C(═O)R₁₂, —NR₁₁S(═O)₂R₁₂,        —S(═O)₂R₁₂, and —S(═O)₂N(R₁₁)₂;    -   R₁₈ is hydrogen, deuterium, halogen, C₁-C₆alkyl, or        C₁-C₆deuteroalkyl; and    -   n is 1, 2, 3, or 4;    -   or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments is a compound of Formula (III), or apharmaceutically acceptable salt or solvate thereof:

In some embodiments is a compound of Formula (IV), or a pharmaceuticallyacceptable salt or solvate thereof:

In some embodiments is a compound of Formula (III) or (IV), or apharmaceutically acceptable salt or solvate thereof, wherein Y is═C(R₁₅)— and Z is ═C(R₁₆)—. In some embodiments is a compound of Formula(III) or (IV), or a pharmaceutically acceptable salt or solvate thereof,wherein Y is =N— and Z is ═C(R₁₆)—. In some embodiments is a compound ofFormula (III) or (IV), or a pharmaceutically acceptable salt or solvatethereof, wherein R₁₆ is selected from hydrogen, halogen, C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆alkoxy, and —CN. In some embodiments is a compoundof Formula (III) or (IV), or a pharmaceutically acceptable salt orsolvate thereof, wherein R₁₆ is selected from hydrogen, halogen, orC₁-C₆alkyl. In some embodiments is a compound of Formula (III) or (IV),or a pharmaceutically acceptable salt or solvate thereof, wherein Y is═C(R₁₅)— and Z is =N—. In some embodiments is a compound of Formula(III) or (IV), or a pharmaceutically acceptable salt or solvate thereof,wherein R₁₅ is selected from hydrogen, halogen, C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆alkoxy, and —CN. In some embodiments is a compoundof Formula (III) or (IV), or a pharmaceutically acceptable salt orsolvate thereof, wherein R₁₅ is selected from hydrogen, halogen, orC₁-C₆alkyl. In some embodiments is a compound of Formula (III) or (IV),or a pharmaceutically acceptable salt or solvate thereof, wherein Y is=N— and Z is ═N—.

In some embodiments is a compound of Formula (I), (II), (III), or (IV),or a pharmaceutically acceptable salt or solvate thereof, wherein X is—O—. In some embodiments is a compound of Formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt or solvate thereof, whereinX is —C(R₉)(R₁₀)—. In some embodiments is a compound of Formula (I),(II), (III), or (IV), or a pharmaceutically acceptable salt or solvatethereof, wherein R₉ and R₁₀ are hydrogen. In some embodiments is acompound of Formula (I), (II), (III), or (IV), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₇ and R₈ are independentlyselected from hydrogen, halogen, C₁-C₆alkyl, —C₁-C₆haloalkyl,C₁-C₆alkoxy, C₂-C₉heteroaryl, —OR₁₁, —N(R₁₁)₂, —CN, —C(═O)OR₁₁,—C(═O)N(R₁₁)₂, —NR₁₁C(═O)R₁₂, —NR₁₁S(═O)₂R₁₂, —S(═O)₂R₁₂, and—S(═O)₂N(R₁₁)₂, wherein C₂-C₉heteroaryl is optionally substituted with1, 2, or 3 groups selected from halogen, C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆alkoxy, and C₁-C₆haloalkoxy. In some embodiments is a compound ofFormula (I), (II), (III), or (IV), or a pharmaceutically acceptable saltor solvate thereof, wherein R₇ and R₈ are independently selected fromhydrogen, halogen, C₁-C₆alkyl, —C₁-C₆haloalkyl, C₂-C₉heteroaryl, —OR₁₁,—CN, —C(═O)N(R₁₁)₂, —NR₁₁S(═O)₂R₁₂, wherein C₂-C₉heteroaryl isoptionally substituted with 1 or 2 groups selected from halogen orC₁-C₆alkyl. In some embodiments is a compound of Formula (I), (II),(III), or (IV), or a pharmaceutically acceptable salt or solvatethereof, wherein R₇ and R₈ are independently selected from hydrogen,halogen, and C₁-C₆alkyl. In some embodiments is a compound of Formula(I), (II), (III), or (IV), or a pharmaceutically acceptable salt orsolvate thereof, wherein R₄ and R₅ are independently selected fromhydrogen and C₁-C₆alkyl. In some embodiments is a compound of Formula(I), (II), (III), or (IV), or a pharmaceutically acceptable salt orsolvate thereof, wherein R₄ is hydrogen and R₅ is C₁-C₆alkyl. In someembodiments is a compound of Formula (I), (II), (III), or (IV), or apharmaceutically acceptable salt or solvate thereof, wherein R₃ ishydrogen. In some embodiments is a compound of Formula (I), (II), (III),or (IV), or a pharmaceutically acceptable salt or solvate thereof,wherein R₆ is hydrogen. In some embodiments is a compound of Formula(I), (II), (III), or (IV), or a pharmaceutically acceptable salt orsolvate thereof, wherein n is 1. In some embodiments is a compound ofFormula (I), (II), (III), or (IV), or a pharmaceutically acceptable saltor solvate thereof, wherein n is 2. In some embodiments is a compound ofFormula (I), (II), (III), or (IV), or a pharmaceutically acceptable saltor solvate thereof, wherein n is 3. In some embodiments is a compound ofFormula (I), (II), (III), or (IV), or a pharmaceutically acceptable saltor solvate thereof, wherein R₁ is hydrogen. In some embodiments is acompound of Formula (I), (II), (III), or (IV), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₂ is hydrogen. In someembodiments is a compound of Formula (I), (II), (III), or (IV), or apharmaceutically acceptable salt or solvate thereof, wherein R₁₈ ishydrogen.

In another aspect described herein is a pharmaceutical compositioncomprising a compound of Formula (I), (II), (III) or (IV), or apharmaceutically acceptable salt or solvate thereof, and apharmaceutically acceptable excipient.

In another aspect described herein is a method of treating aninflammatory or autoimmune disease in a patient in need thereof,comprising administering to the patient a therapeutically effectiveamount of a compound of Formula (I), (II), (III) or (IV), or apharmaceutically acceptable salt or solvate thereof. In some embodimentsis a method of treating an inflammatory or autoimmune disease in apatient in need thereof, comprising administering to the patient atherapeutically effective amount of a compound of Formula (I), (II),(III) or (IV), or a pharmaceutically acceptable salt or solvate thereof,wherein the disease is selected from rheumatoid arthritis, multiplesclerosis, psoriasis, lupus, intestinal bowel disease, Crohn's disease,ulcerative colitis, ankylosing spondylitis, vitiligo, and atopicdermatitis.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.

DETAILED DESCRIPTION OF THE INVENTION Definitions

In the context of this disclosure, a number of terms shall be utilized.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood to which the claimedsubject matter belongs. In the event that there are a plurality ofdefinitions for terms herein, those in this section prevail. Allpatents, patent applications, publications and published nucleotide andamino acid sequences (e.g., sequences available in GenBank or otherdatabases) referred to herein are incorporated by reference. Wherereference is made to a URL or other such identifier or address, it isunderstood that such identifiers can change and particular informationon the internet can come and go, but equivalent information can be foundby searching the internet. Reference thereto evidences the availabilityand public dissemination of such information.

It is to be understood that the foregoing general description and thefollowing detailed description are exemplary and explanatory only andare not restrictive of any subject matter claimed. In this application,the use of the singular includes the plural unless specifically statedotherwise. It must be noted that, as used in the specification and theappended claims, the singular forms “a,” “an” and “the” include pluralreferents unless the context clearly dictates otherwise. In thisapplication, the use of “or” means “and/or” unless stated otherwise.Furthermore, use of the term “including” as well as other forms, such as“include”, “includes,” and “included,” is not limiting.

The section headings used herein are for organizational purposes onlyand are not to be construed as limiting the subject matter described.

Definition of standard chemistry terms may be found in reference works,including but not limited to, Carey and Sundberg “Advanced OrganicChemistry 4^(th) Ed.” Vols. A (2000) and B (2001), Plenum Press, NewYork. Unless otherwise indicated, conventional methods of massspectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinantDNA techniques and pharmacology.

Unless specific definitions are provided, the nomenclature employed inconnection with, and the laboratory procedures and techniques of,analytical chemistry, synthetic organic chemistry, and medicinal andpharmaceutical chemistry described herein are those recognized in thefield. Standard techniques can be used for chemical syntheses, chemicalanalyses, pharmaceutical preparation, formulation, and delivery, andtreatment of patients. Standard techniques can be used for recombinantDNA, oligonucleotide synthesis, and tissue culture and transformation(e.g., electroporation, lipofection). Reactions and purificationtechniques can be performed e.g., using kits of manufacturer'sspecifications or as commonly accomplished in the art or as describedherein. The foregoing techniques and procedures can be generallyperformed of conventional methods and as described in various generaland more specific references that are cited and discussed throughout thepresent specification.

It is to be understood that the methods and compositions describedherein are not limited to the particular methodology, protocols, celllines, constructs, and reagents described herein and as such may vary.It is also to be understood that the terminology used herein is for thepurpose of describing particular embodiments only, and is not intendedto limit the scope of the methods, compounds, compositions describedherein.

As used herein, C₁-C_(x) includes C₁-C₂, C₁-C₃ . . . C₁-C_(x). C₁-C_(x)refers to the number of carbon atoms that make up the moiety to which itdesignates (excluding optional substituents).

An “alkyl” group refers to an aliphatic hydrocarbon group. The alkylgroups may or may not include units of unsaturation. The alkyl moietymay be a “saturated alkyl” group, which means that it does not containany units of unsaturation (i.e. a carbon-carbon double bond or acarbon-carbon triple bond). The alkyl group may also be an “unsaturatedalkyl” moiety, which means that it contains at least one unit ofunsaturation. The alkyl moiety, whether saturated or unsaturated, may bebranched, straight chain, or cyclic.

The “alkyl” group may have 1 to 6 carbon atoms (whenever it appearsherein, a numerical range such as “1 to 6” refers to each integer in thegiven range; e.g., “1 to 6 carbon atoms” means that the alkyl group mayconsist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up toand including 6 carbon atoms, although the present definition alsocovers the occurrence of the term “alkyl” where no numerical range isdesignated). The alkyl group of the compounds described herein may bedesignated as “C₁-C₆alkyl” or similar designations. By way of exampleonly, “C₁-C₆alkyl” indicates that there are one to six carbon atoms inthe alkyl chain, i.e., the alkyl chain is selected from the groupconsisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl,sec-butyl, t-butyl, n-pentyl, iso-pentyl, neo-pentyl, hexyl, propen-3-yl(allyl), cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,cyclohexylmethyl. Alkyl groups can be substituted or unsubstituted.Depending on the structure, an alkyl group can be a monoradical or adiradical (i.e., an alkylene group).

An “alkoxy” refers to a “—O-alkyl” group, where alkyl is as definedherein.

The term “alkenyl” refers to a type of alkyl group in which the firsttwo atoms of the alkyl group form a double bond that is not part of anaromatic group. That is, an alkenyl group begins with the atoms—C(R)═CR₂, wherein R refers to the remaining portions of the alkenylgroup, which may be the same or different. Non-limiting examples of analkenyl group include —CH═CH₂, —C(CH₃)═CH₂, —CH═CHCH₃, —CH═C(CH₃)₂ and—C(CH₃)═CHCH₃. The alkenyl moiety may be branched, straight chain, orcyclic (in which case, it would also be known as a “cycloalkenyl”group). Alkenyl groups may have 2 to 6 carbons. Alkenyl groups can besubstituted or unsubstituted. Depending on the structure, an alkenylgroup can be a monoradical or a diradical (i.e., an alkenylene group).

The term “alkynyl” refers to a type of alkyl group in which the firsttwo atoms of the alkyl group form a triple bond. That is, an alkynylgroup begins with the atoms —C≡C—R, wherein R refers to the remainingportions of the alkynyl group. Non-limiting examples of an alkynyl groupinclude —C≡CH, —C≡CCH₃, —C≡CCH₂CH₃ and —C≡CCH₂CH₂CH₃. The “R” portion ofthe alkynyl moiety may be branched, straight chain, or cyclic. Analkynyl group can have 2 to 6 carbons. Alkynyl groups can be substitutedor unsubstituted. Depending on the structure, an alkynyl group can be amonoradical or a diradical (i.e., an alkynylene group).

“Amino” refers to a —NH₂ group.

The term “alkylamine” or “alkylamino” refers to the —N(alkyl)_(x)H_(y)group, where alkyl is as defined herein and x and y are selected fromthe group x=1, y=1 and x=2, y=0. When x=2, the alkyl groups, takentogether with the nitrogen to which they are attached, can optionallyform a cyclic ring system. “Dialkylamino” refers to a —N(alkyl)₂ group,where alkyl is as defined herein.

The term “aromatic” refers to a planar ring having a delocalizedπ-electron system containing 4n+2 π electrons, where n is an integer.Aromatic rings can be formed from five, six, seven, eight, nine, or morethan nine atoms. Aromatics can be optionally substituted. The term“aromatic” includes both aryl groups (e.g., phenyl, naphthalenyl) andheteroaryl groups (e.g., pyridinyl, quinolinyl).

As used herein, the term “aryl” refers to an aromatic ring wherein eachof the atoms forming the ring is a carbon atom. Aryl rings can be formedby five, six, seven, eight, nine, or more than nine carbon atoms. Arylgroups can be optionally substituted. Examples of aryl groups include,but are not limited to phenyl, and naphthalenyl. Depending on thestructure, an aryl group can be a monoradical or a diradical (i.e., anarylene group).

“Carboxy” refers to —CO₂H. In some embodiments, carboxy moieties may bereplaced with a “carboxylic acid bioisostere”, which refers to afunctional group or moiety that exhibits similar physical and/orchemical properties as a carboxylic acid moiety. A carboxylic acidbioisostere has similar biological properties to that of a carboxylicacid group. A compound with a carboxylic acid moiety can have thecarboxylic acid moiety exchanged with a carboxylic acid bioisostere andhave similar physical and/or biological properties when compared to thecarboxylic acid-containing compound. For example, in one embodiment, acarboxylic acid bioisostere would ionize at physiological pH to roughlythe same extent as a carboxylic acid group. Examples of bioisosteres ofa carboxylic acid include, but are not limited to,

and the like.

The term “cycloalkyl” refers to a monocyclic or polycyclic non-aromaticradical, wherein each of the atoms forming the ring (i.e. skeletalatoms) is a carbon atom. Cycloalkyls may be saturated, or partiallyunsaturated. Cycloalkyls may be fused with an aromatic ring (in whichcase the cycloalkyl is bonded through a non-aromatic ring carbon atom).Cycloalkyl groups include groups having from 3 to 10 ring atoms.

The terms “heteroaryl” or, alternatively, “heteroaromatic” refers to anaryl group that includes one or more ring heteroatoms selected fromnitrogen, oxygen and sulfur. An N-containing “heteroaromatic” or“heteroaryl” moiety refers to an aromatic group in which at least one ofthe skeletal atoms of the ring is a nitrogen atom.

A “heterocycloalkyl” group or “heteroalicyclic” group refers to acycloalkyl group, wherein at least one skeletal ring atom is aheteroatom selected from nitrogen, oxygen and sulfur. The radicals maybe fused with an aryl or heteroaryl. The term heteroalicyclic alsoincludes all ring forms of the carbohydrates, including but not limitedto the monosaccharides, the disaccharides and the oligosaccharides.Unless otherwise noted, heterocycloalkyls have from 2 to 10 carbons inthe ring. It is understood that when referring to the number of carbonatoms in a heterocycloalkyl, the number of carbon atoms in theheterocycloalkyl is not the same as the total number of atoms (includingthe heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atomsof the heterocycloalkyl ring).

The term “halo” or, alternatively, “halogen” means fluoro, chloro, bromoand iodo.

The term “haloalkyl” refers to an alkyl group that is substituted withone or more halogens. The halogens may the same or they may bedifferent. Non-limiting examples of haloalkyls include —CH₂C₁, —CF₃,—CHF₂, —CH₂CF₃, —CF₂CF₃, and the like.

The terms “fluoroalkyl” and “fluoroalkoxy” include alkyl and alkoxygroups, respectively, that are substituted with one or more fluorineatoms. Non-limiting examples of fluoroalkyls include —CF₃, —CHF₂, —CH₂F,—CH₂CF₃, —CF₂CF₃, —CF₂CF₂CF₃, —CF(CH₃)₃, and the like. Non-limitingexamples of fluoroalkoxy groups, include —OCF₃, —OCHF₂, —OCH₂F,—OCH₂CF₃, —OCF₂CF₃, —OCF₂CF₂CF₃, —OCF(CH₃)₂, and the like.

The term “deuteroalkyl” refers to an alkyl group that is substitutedwith one or more deuteriums.

The term “heteroalkyl” refers to an alkyl radical where one or moreskeletal chain atoms is selected from an atom other than carbon, e.g.,oxygen, nitrogen, sulfur, phosphorus, silicon, or combinations thereof.The heteroatom(s) may be placed at any interior position of theheteroalkyl group. Examples include, but are not limited to, —CH₂—O—CH₃,—CH₂—CH₂—O—CH₃, —CH₂—NH—CH₃, —CH₂—CH₂—NH—CH₃, —CH₂—N(CH₃)—CH₃,—CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃, —CH₂—CH₂—S(O)—CH₃,—CH₂—CH₂—S(O)₂—CH₃, —CH₂—NH—OCH₃, —CH₂—O—Si(CH₃)₃, —CH₂—CH═N—OCH₃, and—CH═CH—N(CH₃)—CH₃. In addition, up to two heteroatoms may beconsecutive, such as, by way of example, —CH₂—NH—OCH₃ and—CH₂—O—Si(CH₃)₃. Excluding the number of heteroatoms, a “heteroalkyl”may have from 1 to 6 carbon atoms.

The term “bond” or “single bond” refers to a chemical bond between twoatoms, or two moieties when the atoms joined by the bond are consideredto be part of larger substructure.

The term “moiety” refers to a specific segment or functional group of amolecule. Chemical moieties are often recognized chemical entitiesembedded in or appended to a molecule.

As used herein, the substituent “R” appearing by itself and without anumber designation refers to a substituent selected from among fromalkyl, haloalkyl, heteroalkyl, alkenyl, cycloalkyl, aryl, heteroaryl(bonded through a ring carbon), and heterocycloalkyl.

“Optional” or “optionally” means that a subsequently described event orcircumstance may or may not occur and that the description includesinstances when the event or circumstance occurs and instances in whichit does not.

The term “optionally substituted” or “substituted” means that thereferenced group may be substituted with one or more additional group(s)individually and independently selected from alkyl, cycloalkyl, aryl,heteroaryl, heterocycloalkyl, —OH, alkoxy, aryloxy, alkylthio, arylthio,alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, —CN, alkyne,C₁-C₆alkylalkyne, halo, acyl, acyloxy, —CO₂H, —CO₂-alkyl, nitro,haloalkyl, fluoroalkyl, and amino, including mono- and di-substitutedamino groups (e.g. —NH₂, —NHR, —N(R)₂), and the protected derivativesthereof. By way of example, an optional substituents may be L^(s)R^(s),wherein each L^(s) is independently selected from a bond, —O—, —C(═O)—,—S—, —S(═O)—, —S(═O)₂—, —NH—, —NHC(O)—, —C(O)NH—, S(═O)₂NH—, —NHS(═O)₂,—OC(O)NH—, —NHC(O)O—, —(C₁-C₆alkyl)-, or —(C₂-C₆alkenyl)-; and eachR^(s) is independently selected from among H, (C₁-C₆alkyl),(C₃-C₈cycloalkyl), aryl, heteroaryl, heterocycloalkyl, andC₁-C₆heteroalkyl. The protecting groups that may form the protectivederivatives of the above substituents are found in sources such asGreene and Wuts, above.

As used herein, the term “about” or “approximately” means within 20%,preferably within 10%, and more preferably within 5% of a given value orrange.

The term a “therapeutically effective amount” as used herein refers tothe amount of a TYK2 pseudokinase ligand that, when administered to amammal in need, is effective to at least partially ameliorate or to atleast partially prevent conditions related to skin aging.

As used herein, the term “expression” includes the process by whichpolynucleotides are transcribed into mRNA and translated into peptides,polypeptides, or proteins.

The term “modulate” encompasses either a decrease or an increase inactivity or expression depending on the target molecule.

The term “activator” is used in this specification to denote anymolecular species that results in activation of the indicated receptor,regardless of whether the species itself binds to the receptor or ametabolite of the species binds to the receptor when the species isadministered topically. Thus, the activator can be a ligand of thereceptor or it can be an activator that is metabolized to the ligand ofthe receptor, i.e., a metabolite that is formed in tissue and is theactual ligand.

The term “patient” or “mammal” refers to a human, a non-human primate,canine, feline, bovine, ovine, porcine, murine, or other veterinary orlaboratory mammal. Those skilled in the art recognize that a therapywhich reduces the severity of a pathology in one species of mammal ispredictive of the effect of the therapy on another species of mammal.

The term “soft-drug” as used herein, refers to drug substance and/or achemical compound that is biologically active in the desired targettissue and that is metabolized, after exerting its effect in the targettissue, to a compound that is inactive against the biological target. Insome embodiments, the soft-drug has no target biological activity insystemic circulation.

“Pharmaceutically acceptable salt” includes both acid and base additionsalts. A pharmaceutically acceptable salt of any one of the compoundsdescribed herein is intended to encompass any and all pharmaceuticallysuitable salt forms. Preferred pharmaceutically acceptable salts of thecompounds described herein are pharmaceutically acceptable acid additionsalts, and pharmaceutically acceptable base addition salts.

“Pharmaceutically acceptable acid addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freebases, which are not biologically or otherwise undesirable, and whichare formed with inorganic acids such as hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid,hydrofluoric acid, phosphorous acid, and the like. Also included aresalts that are formed with organic acids such as aliphatic mono- anddicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoicacids, alkanedioic acids, aromatic acids, aliphatic and aromaticsulfonic acids, etc. and include, for example, acetic acid,trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid,oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid, and the like. Exemplary salts thus include sulfates,pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates,monohydrogenphosphates, dihydrogenphosphates, metaphosphates,pyrophosphates, chlorides, bromides, iodides, acetates,trifluoroacetates, propionates, caprylates, isobutyrates, oxalates,malonates, succinate suberates, sebacates, fumarates, maleates,mandelates, benzoates, chlorobenzoates, methylbenzoates,dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates,phenylacetates, citrates, lactates, malates, tartrates,methanesulfonates, and the like. Also contemplated are salts of aminoacids, such as arginates, gluconates, and galacturonates (see, forexample, Berge S. M. et al., “Pharmaceutical Salts,” Journal ofPharmaceutical Science, 66:1-19 (1997)). Acid addition salts of basiccompounds are prepared by contacting the free base forms with asufficient amount of the desired acid to produce the salt.

“Pharmaceutically acceptable base addition salt” refers to those saltsthat retain the biological effectiveness and properties of the freeacids, which are not biologically or otherwise undesirable. These saltsare prepared from addition of an inorganic base or an organic base tothe free acid. In some embodiments, pharmaceutically acceptable baseaddition salts are formed with metals or amines, such as alkali andalkaline earth metals or organic amines. Salts derived from inorganicbases include, but are not limited to, sodium, potassium, lithium,ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminumsalts, and the like. Salts derived from organic bases include, but arenot limited to, salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, for example,isopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol,2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine,caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine,hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline,N-methylglucamine, glucosamine, methylglucamine, theobromine, purines,piperazine, piperidine, N-ethylpiperidine, polyamine resins, and thelike. See Berge et al., supra.

As used herein, “treatment” or “treating” or “palliating” or“ameliorating” are used interchangeably herein. These terms refer to anapproach for obtaining beneficial or desired results including but notlimited to therapeutic benefit and/or a prophylactic benefit. By“therapeutic benefit” is meant eradication or amelioration of theunderlying disorder being treated. Also, a therapeutic benefit isachieved with the eradication or amelioration of one or more of thephysiological symptoms associated with the underlying disorder such thatan improvement is observed in the patient, notwithstanding that thepatient is still afflicted with the underlying disorder. Forprophylactic benefit, the compositions are administered to a patient atrisk of developing a particular disease, or to a patient reporting oneor more of the physiological symptoms of a disease, even though adiagnosis of this disease has not been made.

TYK2 Pseudokinase Ligands

As a member of the JAK family of tyrosine kinases, TYK2 mediates thesignaling of pro-inflammatory cytokines and therefore represents atarget for treating various inflammatory and autoimmune diseases. Thehallmark structural feature of the JAK family is the pseudokinase (JH2)domain immediately N-terminal to the catalytic domain (JH1). Althoughthe JH2 domain shares the overall fold of a typical catalytic domain, aseries of individual residue and conformational differences between theTYK2 JH1 and JH2 domains points to the lack of catalytic activity of theJH2 domain. The JH2 domains of the JAK family have been shown toregulate the function of the JH1 domains. The overall body of evidenceis consistent with the TYK2 pseudokinase domain being auto-inhibitory,stabilizing the inactivated state of the kinase domain and that smallmolecule ligands can stabilize this auto-inhibitory conformation therebypreventing protein function in an allosteric manner (Moslin et al., Med.Chem. Commun., 2017, 700-712).

The compounds of Formula (I), (II), (III), (IIIa), (IIIb), (IIIc),(IIId), (IV), (IVa), (IVb), (IVc), or (IVd) described herein are TYK2pseudokinase ligands. The compounds of Formula (I), (II), (III), (IIIa),(IIIb), (IIIc), (IIId), (IV), (IVa), (IVb), (IVc), or (IVd) describedherein, and compositions comprising these compounds, are useful for thetreatment of an inflammatory or autoimmune disease.

In some embodiments, provided herein is a compound of Formula (I), or apharmaceutically acceptable salt or solvate thereof:

wherein:

-   -   is C₃-C₆cycloalkyl, C₆-C₁₀aryl, C₂-C₉heterocycloalkyl, or        C₂-C₉heteroaryl, wherein C₃-C₆cycloalkyl, C₆-C₁₀aryl,        C₂-C₉heterocycloalkyl, or C₂-C₉heteroaryl is optionally        substituted with 1, 2, 3, or 4 R₇;    -   X is —O—, —C(R₉)(R₁₀)—, —C(R₉)(R₁₀)—O—, —O—C(R₉)(R₁₀), —C(O)—,        —C(O)N(R₃)—, —N(R₃)C(O)—, or —N(R₁₇)—;    -   L₁ is —C(O)N(R₃)—, —N(R₃)C(O)—, —C(R₉)(R₁₀)—O—, or        —O—C(R₉)(R₁₀)—;    -   L₂ is —N(R₆)—, —N(R₆)CH₂—, or —CH₂N(R₆)—;    -   each R₁ is independently selected from hydrogen, deuterium,        C₁-C₆alkyl, and C₁-C₆deuteroalkyl;    -   each R₂ is independently selected from hydrogen, deuterium,        C₁-C₆alkyl, and C₁-C₆deuteroalkyl; or R₁ and R₂ are combined to        form a 3-, 4-, 5-, or 6-membered cycloalkyl ring or a 4-, 5-, or        6-membered heterocycloalkyl ring;    -   each R₃ is independently hydrogen or C₁-C₆alkyl; or R₂ and R₃        together with the atoms to which they are attached are combined        to form a 5- or 6-membered heterocycloalkyl ring optionally        substituted 1, 2, or 3 with groups selected from halogen, —OH,        C₁-C₆alkyl, and —C₁-C₆alkyl-OH;    -   R₄ is selected from hydrogen, deuterium, C₁-C₆alkyl,        C₁-C₆deuteroalkyl, C₁-C₆heteroalkyl, C₃-C₆cycloalkyl, and        C₂-C₉heterocycloalkyl;    -   R₅ is selected from hydrogen, deuterium, C₁-C₆alkyl,        C₁-C₆deuteroalkyl, C₁-C₆heteroalkyl, C₃-C₆cycloalkyl, and        C₂-C₉heterocycloalkyl;    -   R₁₃ is hydrogen, deuterium, C₁-C₆alkyl, or C₁-C₆deuteroalkyl; or        R₅ and R₁₃ together with the atoms to which they are attached        are combined to form a 5- or 6-membered heterocycloalkyl ring or        a 5- or 6-membered heteroaryl ring, wherein the 5- or 6-membered        heterocycloalkyl ring or 5- or 6-membered heteroaryl ring is        optionally substituted with 1, 2, or 3 groups selected from        halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, and        C₁-C₆haloalkoxy;    -   R₆ is hydrogen or C₁-C₆alkyl;    -   each R₇ is independently selected from deuterium, halogen,        C₁-C₆alkyl, C₁-C₆deuteroalkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy,        C₁-C₆heteroalkyl, oxo, —OR₁₁, —N(R₁₁)₂, —CN, —C(═O)R₁₂,        —C(═O)OR₁₁, —C(═O)N(R₁₁)₂, —NR₁₁C(═O)R₁₂, —NR₁₁S(═O)₂R₁₂,        —S(═O)₂R₁₂, and —S(═O)₂N(R₁₁)₂;    -   each R₉ and each R₁₀ are independently selected from hydrogen,        deuterium, C₁-C₆alkyl, and C₁-C₆deuteroalkyl;    -   each R₁ is independently selected from hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆heteroalkyl, and phenyl, wherein phenyl is        optionally substituted with 1, 2, or 3 groups selected from        halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy,        C₁-C₆haloalkoxy, C₂-C₉heterocycloalkyl, C₂-C₉heteroaryl, —OR₁₄,        —N(R₁₄)₂, —C(═O)OR₁₄, and —C(═O)N(R₁₄)₂;    -   each R₁₂ is independently selected from C₁-C₆alkyl and        C₁-C₆heteroalkyl;    -   each R₁₄ is independently selected from hydrogen, C₁-C₆alkyl,        and C₁-C₆haloalkyl;    -   R₁₇ is hydrogen or C₁-C₆alkyl;    -   R₁₈ is hydrogen, deuterium, halogen, C₁-C₆alkyl, or        C₁-C₆deuteroalkyl; and    -   n is 1, 2, 3, or 4.

In some embodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, wherein

is C₆-C₁₀aryl optionally substituted with 1, 2, or 3 R₇. In someembodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, wherein

is phenyl optionally substituted with 1, 2, or 3 R₇. In some embodimentsis a compound of Formula (I), or a pharmaceutically acceptable salt orsolvate thereof wherein

is C₂-C₉heteroaryl optionally substituted with 1, 2, or 3 R₇. In someembodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, wherein

is C₂-C₉heteroaryl selected from oxazolyl, thiazolyl, pyrazolyl,furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, isoxazolyl,isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl,wherein oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl,imidazolyl, triazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl,pyrazinyl, and pyridazinyl are optionally substituted with 1, 2, or 3R₇. In some embodiments is a compound of Formula (I), or apharmaceutically acceptable salt or solvate thereof, wherein R₇ isselected from halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, and —CN.In some embodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, wherein

is C₂-C₉heteroaryl selected from:

In some embodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, wherein

is C₂-C₉heterocycloalkyl optionally substituted with 1, 2, or 3 R₇. Insome embodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, wherein

is C₃-C₆cycloalkyl optionally substituted with 1, 2, 3, or 4 R₇. In someembodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₇ is selected from halogen,C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, and oxo. In some embodiments isa compound of Formula (I), or a pharmaceutically acceptable salt orsolvate thereof, wherein

is C₂-C₉heterocycloalkyl selected from:

In some embodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, wherein L₁ is —C(O)N(R₃)—. In someembodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, wherein L₁ is —N(R₃)C(O)—. In someembodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, wherein L₁ is —C(R₉)(R₁₀)—O—. Insome embodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, wherein L₁ is —O—C(R₉)(R₁₀)—.

In some embodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, wherein L₂ is —N(R₆)—. In someembodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, wherein L₂ is —N(H)—. In someembodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, wherein L₂ is —N(R₆)CH₂—. In someembodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, wherein L₂ is —N(H)CH₂—. In someembodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, wherein L₂ is —CH₂N(R₆)—. In someembodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, wherein L₂ is —CH₂N(H)—.

In some embodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, wherein X is —O—. In someembodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, wherein X is —O— and n is 2. In someembodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, wherein X is —O—, n is 2, and eachR₁ and each R₂ are hydrogen. In some embodiments is a compound ofFormula (I), or a pharmaceutically acceptable salt or solvate thereof,wherein X is —O—, n is 2, each R₁ is hydrogen, and one R₂ is hydrogenand one R₂ is C₁-C₆alkyl. In some embodiments is a compound of Formula(I), or a pharmaceutically acceptable salt or solvate thereof, wherein Xis —O— and n is 3. In some embodiments is a compound of Formula (I), ora pharmaceutically acceptable salt or solvate thereof, wherein X is —O—,n is 3, and each R₁ and each R₂ are hydrogen. In some embodiments is acompound of Formula (I), or a pharmaceutically acceptable salt orsolvate thereof, wherein X is —O—, n is 3, one R₁ is C₁-C₆alkyl and oneR₂ is C₁-C₆alkyl and the remaining R₁ and R₂ are each hydrogen.

In some embodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, wherein X is —C(R₉)(R₁₀)—. In someembodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, wherein X is —CH₂—. In someembodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, wherein X is —CH₂— and n is 1. Insome embodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, wherein X is —CH₂—, n is 1, and R₁and R₂ are hydrogen. In some embodiments is a compound of Formula (I),or a pharmaceutically acceptable salt or solvate thereof, wherein X is—CH₂— and n is 2. In some embodiments is a compound of Formula (I), or apharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—,n is 2, and each R₁ and each R₂ are hydrogen. In some embodiments is acompound of Formula (I), or a pharmaceutically acceptable salt orsolvate thereof, wherein X is —CH₂— and n is 3. In some embodiments is acompound of Formula (I), or a pharmaceutically acceptable salt orsolvate thereof, wherein X is —CH₂—, n is 3, and each R₁ and each R₂ arehydrogen.

In some embodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, wherein X is —N(R₁₇)—. In someembodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, wherein X is —N(H)—. In someembodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, wherein X is —N(H)— and n is 1. Insome embodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, wherein X is —N(H)—, n is 1, and R₁and R₂ are hydrogen. In some embodiments is a compound of Formula (I),or a pharmaceutically acceptable salt or solvate thereof, wherein X is—N(H)— and n is 2. In some embodiments is a compound of Formula (I), ora pharmaceutically acceptable salt or solvate thereof, wherein X is—N(H)—, n is 2, and each R₁ and each R₂ are hydrogen. In someembodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, wherein X is —N(H)— and n is 3. Insome embodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, wherein X is —N(H)—, n is 3, andeach R₁ and each R₂ are hydrogen.

In some embodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, wherein X is —C(R₉)(R₁₀)—O—. In someembodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, wherein X is —CH₂O— and n is 1. Insome embodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, wherein X is —CH₂O—, n is 1, and R₁and R₂ are hydrogen. In some embodiments is a compound of Formula (I),or a pharmaceutically acceptable salt or solvate thereof, wherein X is—CH₂O— and n is 2. In some embodiments is a compound of Formula (I), ora pharmaceutically acceptable salt or solvate thereof, wherein X is—CH₂O—, n is 2, and each R₁ and each R₂ are hydrogen. In someembodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, wherein X is —CH₂O— and n is 3. Insome embodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, wherein X is —CH₂O—, n is 3, andeach R₁ and each R₂ are hydrogen.

In some embodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₄ is selected from hydrogenand C₁-C₆alkyl. In some embodiments is a compound of Formula (I), or apharmaceutically acceptable salt or solvate thereof, wherein R₄ ishydrogen. In some embodiments is a compound of Formula (I), or apharmaceutically acceptable salt or solvate thereof, wherein R₄ isC₁-C₆alkyl.

In some embodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₅ is selected from hydrogenand C₁-C₆alkyl. In some embodiments is a compound of Formula (I), or apharmaceutically acceptable salt or solvate thereof, wherein R₅ ishydrogen. In some embodiments is a compound of Formula (I), or apharmaceutically acceptable salt or solvate thereof, wherein R₅ isC₁-C₆alkyl.

In some embodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₁₃ is hydrogen. In someembodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₅ and R₁₃ together with theatoms to which they are attached are combined to form a 5- or 6-memberedheterocycloalkyl ring or a 5- or 6-membered heteroaryl ring, wherein the5- or 6-membered heterocycloalkyl ring or 5- or 6-membered heteroarylring is optionally substituted with 1, 2, or 3 groups selected fromhalogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, and C₁-C₆haloalkoxy.In some embodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₅ and R₁₃ together with theatoms to which they are attached are combined to form a 5- or 6-memberedheterocycloalkyl ring, wherein the 5- or 6-membered heterocycloalkylring is optionally substituted with 1, 2, or 3 groups selected fromhalogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, and C₁-C₆haloalkoxy.In some embodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₅ and R₁₃ together with theatoms to which they are attached are combined to form a 5- or 6-memberedheteroaryl ring, wherein the 5- or 6-membered heteroaryl ring isoptionally substituted with 1, 2, or 3 groups selected from halogen,C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, and C₁-C₆haloalkoxy.

In some embodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₄ is hydrogen and R₅ isC₁-C₆alkyl. In some embodiments is a compound of Formula (I), or apharmaceutically acceptable salt or solvate thereof, wherein R₄ and R₅are hydrogen. In some embodiments is a compound of Formula (I), or apharmaceutically acceptable salt or solvate thereof, wherein R₄ and R₅are C₁-C₆alkyl.

In some embodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, wherein each R₃ is hydrogen. In someembodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, wherein each R₃ is C₁-C₆alkyl. Insome embodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₂ and R₃ together with theatoms to which they are attached are combined to form a 5- or 6-memberedheterocycloalkyl ring optionally substituted 1, 2, or 3 with groupsselected from halogen, —OH, C₁-C₆alkyl, and —C₁-C₆alkyl-OH.

In some embodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₁₈ is hydrogen. In someembodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₁₈ is deuterium. In someembodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₁₈ is halogen. In someembodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₁₈ is C₁-C₆alkyl. In someembodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₁₈ is C₁-C₆deuteroalkyl.

In some embodiments, provided herein is a compound of Formula (II), or apharmaceutically acceptable salt or solvate thereof:

wherein:

-   -   is C₃-C₆cycloalkyl, C₆-C₁₀aryl, C₂-C₉heterocycloalkyl, or        C₂-C₉heteroaryl, wherein C₃-C₆cycloalkyl, C₆-C₁₀aryl,        C₂-C₉heterocycloalkyl, or C₂-C₉heteroaryl is optionally        substituted with 1, 2, 3, or 4 R₇;    -   X is —O—, —C(R₉)(R₁₀)—, —C(R₉)(R₁₀)—O—, —O—C(R₉)(R₁₀), —C(O)—,        —C(O)N(R₃)—, —N(R₃)C(O)—, or —N(R₁₇)—;    -   L₁ is —C(O)N(R₃)—, —N(R₃)C(O)—, —C(R₉)(R₁₀)—O—, or        —O—C(R₉)(R₁₀)—;    -   L₂ is —N(R₆)—, —N(R₆)CH₂—, or —CH₂N(R₆)—;    -   each R₁ is independently selected from hydrogen, deuterium,        C₁-C₆alkyl, and C₁-C₆deuteroalkyl;    -   each R₂ is independently selected from hydrogen, deuterium,        C₁-C₆alkyl, and C₁-C₆deuteroalkyl; or R₁ and R₂ are combined to        form a 3-, 4-, 5-, or 6-membered cycloalkyl ring or a 4-, 5-, or        6-membered heterocycloalkyl ring;    -   each R₃ is independently hydrogen or C₁-C₆alkyl; or R₂ and R₃        together with the atoms to which they are attached are combined        to form a 5- or 6-membered heterocycloalkyl ring optionally        substituted 1, 2, or 3 with groups selected from halogen, —OH,        C₁-C₆alkyl, and —C₁-C₆alkyl-OH;    -   R₄ is selected from hydrogen, deuterium, C₁-C₆alkyl,        C₁-C₆deuteroalkyl, C₁-C₆heteroalkyl, C₃-C₆cycloalkyl, and        C₂-C₉heterocycloalkyl;    -   R₅ is selected from hydrogen, deuterium, C₁-C₆alkyl,        C₁-C₆deuteroalkyl, C₁-C₆heteroalkyl, C₃-C₆cycloalkyl, and        C₂-C₉heterocycloalkyl;    -   R₁₃ is hydrogen, deuterium, C₁-C₆alkyl, or C₁-C₆deuteroalkyl; or        R₅ and R₁₃ together with the atoms to which they are attached        are combined to form a 5- or 6-membered heterocycloalkyl ring or        a 5- or 6-membered heteroaryl ring, wherein the 5- or 6-membered        heterocycloalkyl ring or 5- or 6-membered heteroaryl ring is        optionally substituted with 1, 2, or 3 groups selected from        halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, and        C₁-C₆haloalkoxy;    -   R₆ is hydrogen or C₁-C₆alkyl;    -   each R₇ is independently selected from deuterium, halogen,        C₁-C₆alkyl, C₁-C₆deuteroalkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy,        C₁-C₆heteroalkyl, oxo, —OR₁₁, —N(R₁₁)₂, —CN, —C(═O)R₁₂,        —C(═O)OR₁₁, —C(═O)N(R₁₁)₂, —NR₁₁C(═O)R₁₂, —NR₁₁S(═O)₂R₁₂,        —S(═O)₂R₁₂, and —S(═O)₂N(R₁₁)₂;    -   each R₉ and each R₁₀ are independently selected from hydrogen,        deuterium, C₁-C₆alkyl, and C₁-C₆deuteroalkyl;    -   each R₁ is independently selected from hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆heteroalkyl, and phenyl, wherein phenyl is        optionally substituted with 1, 2, or 3 groups selected from        halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy,        C₁-C₆haloalkoxy, C₂-C₉heterocycloalkyl, C₂-C₉heteroaryl, —OR₁₄,        —N(R₁₄)₂, —C(═O)OR₁₄, and —C(═O)N(R₁₄)₂;    -   each R₁₂ is independently selected from C₁-C₆alkyl and        C₁-C₆heteroalkyl;    -   each R₁₄ is independently selected from hydrogen, C₁-C₆alkyl,        and C₁-C₆haloalkyl;    -   R₁₇ is hydrogen or C₁-C₆alkyl;    -   R₁₈ is hydrogen, deuterium, halogen, C₁-C₆alkyl, or        C₁-C₆deuteroalkyl; and    -   n is 1, 2, 3, or 4.

In some embodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt or solvate thereof, wherein

is C₆-C₁₀aryl optionally substituted with 1, 2, or 3 R₇. In someembodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt or solvate thereof, wherein

is phenyl optionally substituted with 1, 2, or 3 R₇. In some embodimentsis a compound of Formula (II), or a pharmaceutically acceptable salt orsolvate thereof, wherein

is C₂-C₉heteroaryl optionally substituted with 1, 2, or 3 R₇. In someembodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt or solvate thereof, wherein

is C₂-C₉heteroaryl selected from oxazolyl, thiazolyl, pyrazolyl,furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, isoxazolyl,isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl,wherein oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl,imidazolyl, triazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl,pyrazinyl, and pyridazinyl are optionally substituted with 1, 2, or 3R₇. In some embodiments is a compound of Formula (II), or apharmaceutically acceptable salt or solvate thereof, wherein R₇ isselected from halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, and —CN.In some embodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt or solvate thereof, wherein

is C₂-C₉heteroaryl selected from:

In some embodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt or solvate thereof, wherein

is C₂-C₉heterocycloalkyl optionally substituted with 1, 2, or 3 R₇. Insome embodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt or solvate thereof, wherein

is C₃-C₆cycloalkyl optionally substituted with 1, 2, 3, or 4 R₇. In someembodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₇ is selected from halogen,C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, and oxo. In some embodiments isa compound of Formula (II), or a pharmaceutically acceptable salt orsolvate thereof, wherein

is C₂-C₉heterocycloalkyl selected from:

In some embodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt or solvate thereof, wherein L₁ is —C(O)N(R₃)—. In someembodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt or solvate thereof, wherein L₁ is —N(R₃)C(O)—. In someembodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt or solvate thereof, wherein L₁ is —C(R₉)(R₁₀)—O—. Insome embodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt or solvate thereof, wherein L₁ is —O—C(R₉)(R₁₀)—.

In some embodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt or solvate thereof, wherein L₂ is —N(R₆)—. In someembodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt or solvate thereof, wherein L₂ is —N(H)—. In someembodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt or solvate thereof, wherein L₂ is —N(R₆)CH₂—. In someembodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt or solvate thereof, wherein L₂ is —N(H)CH₂—. In someembodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt or solvate thereof, wherein L₂ is —CH₂N(R₆)—. In someembodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt or solvate thereof, wherein L₂ is —CH₂N(H)—.

In some embodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt or solvate thereof, wherein X is —O—. In someembodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt or solvate thereof, wherein X is —O— and n is 2. In someembodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt or solvate thereof, wherein X is —O—, n is 2, and eachR₁ and each R₂ are hydrogen. In some embodiments is a compound ofFormula (II), or a pharmaceutically acceptable salt or solvate thereof,wherein X is —O—, n is 2, each R₁ is hydrogen, and one R₂ is hydrogenand one R₂ is C₁-C₆alkyl. In some embodiments is a compound of Formula(II), or a pharmaceutically acceptable salt or solvate thereof, whereinX is —O— and n is 3. In some embodiments is a compound of Formula (II),or a pharmaceutically acceptable salt or solvate thereof, wherein X is—O—, n is 3, and each R₁ and each R₂ are hydrogen. In some embodimentsis a compound of Formula (II), or a pharmaceutically acceptable salt orsolvate thereof, wherein X is —O—, n is 3, one R₁ is C₁-C₆alkyl and oneR₂ is C₁-C₆alkyl and the remaining R₁ and R₂ are each hydrogen.

In some embodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt or solvate thereof, wherein X is —C(R₉)(R₁₀)—. In someembodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt or solvate thereof, wherein X is —CH₂—. In someembodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt or solvate thereof, wherein X is —CH₂— and n is 1. Insome embodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt or solvate thereof, wherein X is —CH₂—, n is 1, and R₁and R₂ are hydrogen. In some embodiments is a compound of Formula (II),or a pharmaceutically acceptable salt or solvate thereof, wherein X is—CH₂— and n is 2. In some embodiments is a compound of Formula (II), ora pharmaceutically acceptable salt or solvate thereof, wherein X is—CH₂—, n is 2, and each R₁ and each R₂ are hydrogen. In some embodimentsis a compound of Formula (II), or a pharmaceutically acceptable salt orsolvate thereof, wherein X is —CH₂— and n is 3. In some embodiments is acompound of Formula (II), or a pharmaceutically acceptable salt orsolvate thereof, wherein X is —CH₂—, n is 3, and each R₁ and each R₂ arehydrogen.

In some embodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt or solvate thereof, wherein X is —N(R₁₇)—. In someembodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt or solvate thereof, wherein X is —N(H)—. In someembodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt or solvate thereof, wherein X is —N(H)— and n is 1. Insome embodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt or solvate thereof, wherein X is —N(H)—, n is 1, and R₁and R₂ are hydrogen. In some embodiments is a compound of Formula (II),or a pharmaceutically acceptable salt or solvate thereof, wherein X is—N(H)— and n is 2. In some embodiments is a compound of Formula (II), ora pharmaceutically acceptable salt or solvate thereof, wherein X is—N(H)—, n is 2, and each R₁ and each R₂ are hydrogen. In someembodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt or solvate thereof, wherein X is —N(H)— and n is 3. Insome embodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt or solvate thereof, wherein X is —N(H)—, n is 3, andeach R₁ and each R₂ are hydrogen.

In some embodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt or solvate thereof, wherein X is —C(R₉)(R₁₀)—O—. In someembodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt or solvate thereof, wherein X is —CH₂O— and n is 1. Insome embodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt or solvate thereof, wherein X is —CH₂O—, n is 1, and R₁and R₂ are hydrogen. In some embodiments is a compound of Formula (II),or a pharmaceutically acceptable salt or solvate thereof, wherein X is—CH₂O— and n is 2. In some embodiments is a compound of Formula (II), ora pharmaceutically acceptable salt or solvate thereof, wherein X is—CH₂O—, n is 2, and each R₁ and each R₂ are hydrogen. In someembodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt or solvate thereof, wherein X is —CH₂O— and n is 3. Insome embodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt or solvate thereof, wherein X is —CH₂O—, n is 3, andeach R₁ and each R₂ are hydrogen.

In some embodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₄ is selected from hydrogenand C₁-C₆alkyl. In some embodiments is a compound of Formula (II), or apharmaceutically acceptable salt or solvate thereof, wherein R₄ ishydrogen. In some embodiments is a compound of Formula (II), or apharmaceutically acceptable salt or solvate thereof, wherein R₄ isC₁-C₆alkyl.

In some embodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₅ is selected from hydrogenand C₁-C₆alkyl. In some embodiments is a compound of Formula (II), or apharmaceutically acceptable salt or solvate thereof, wherein R₅ ishydrogen. In some embodiments is a compound of Formula (II), or apharmaceutically acceptable salt or solvate thereof, wherein R₅ isC₁-C₆alkyl.

In some embodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₁₃ is hydrogen. In someembodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₅ and R₁₃ together with theatoms to which they are attached are combined to form a 5- or 6-memberedheterocycloalkyl ring or a 5- or 6-membered heteroaryl ring, wherein the5- or 6-membered heterocycloalkyl ring or 5- or 6-membered heteroarylring is optionally substituted with 1, 2, or 3 groups selected fromhalogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, and C₁-C₆haloalkoxy.In some embodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₅ and R₁₃ together with theatoms to which they are attached are combined to form a 5- or 6-memberedheterocycloalkyl ring, wherein the 5- or 6-membered heterocycloalkylring is optionally substituted with 1, 2, or 3 groups selected fromhalogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, and C₁-C₆haloalkoxy.In some embodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₅ and R₁₃ together with theatoms to which they are attached are combined to form a 5- or 6-memberedheteroaryl ring, wherein the 5- or 6-membered heteroaryl ring isoptionally substituted with 1, 2, or 3 groups selected from halogen,C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, and C₁-C₆haloalkoxy.

In some embodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₄ is hydrogen and R₅ isC₁-C₆alkyl. In some embodiments is a compound of Formula (II), or apharmaceutically acceptable salt or solvate thereof, wherein R₄ and R₅are hydrogen. In some embodiments is a compound of Formula (II), or apharmaceutically acceptable salt or solvate thereof, wherein R₄ and R₅are C₁-C₆alkyl.

In some embodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt or solvate thereof, wherein each R₃ is hydrogen. In someembodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt or solvate thereof, wherein each R₃ is C₁-C₆alkyl. Insome embodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₂ and R₃ together with theatoms to which they are attached are combined to form a 5- or 6-memberedheterocycloalkyl ring optionally substituted 1, 2, or 3 with groupsselected from halogen, —OH, C₁-C₆alkyl, and —C₁-C₆alkyl-OH.

In some embodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₁₈ is hydrogen. In someembodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₁₈ is deuterium. In someembodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₁₈ is halogen. In someembodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₁₈ is C₁-C₆alkyl. In someembodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₁₈ is C₁-C₆deuteroalkyl.

In some embodiments, provided herein is a compound of Formula (III), ora pharmaceutically acceptable salt or solvate thereof:

wherein.

-   -   X is —O— or —C(R₉)(R₁₀)—;    -   Y is ═N— or ═C(R₁₅)—;    -   Z is ═N— or ═C(R₁₆)—;    -   each R₁ is independently selected from hydrogen, deuterium,        C₁-C₆alkyl, and C₁-C₆deuteroalkyl;    -   each R₂ is independently selected from hydrogen, deuterium,        C₁-C₆alkyl, and C₁-C₆deuteroalkyl;    -   R₃ is hydrogen or C₁-C₆alkyl;    -   R₄ is selected from hydrogen, deuterium, C₁-C₆alkyl,        C₁-C₆deuteroalkyl, C₁-C₆heteroalkyl, C₃-C₆cycloalkyl, and        C₂-C₉heterocycloalkyl;    -   R₅ is selected from hydrogen, deuterium, C₁-C₆alkyl,        C₁-C₆deuteroalkyl, C₁-C₆heteroalkyl, C₃-C₆cycloalkyl, and        C₂-C₉heterocycloalkyl;    -   R₁₃ is hydrogen, deuterium, C₁-C₆alkyl, or C₁-C₆deuteroalkyl; or        R₅ and R₁₃ together with the atoms to which they are attached        are combined to form a 5- or 6-membered heterocycloalkyl ring or        a 5- or 6-membered heteroaryl ring, wherein the 5- or 6-membered        heterocycloalkyl ring or 5- or 6-membered heteroaryl ring is        optionally substituted with 1, 2, or 3 groups selected from        halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, and        C₁-C₆haloalkoxy;    -   R₆ is hydrogen or C₁-C₆alkyl;    -   R₇ and R₈ are independently selected from hydrogen, deuterium,        halogen, C₁-C₆alkyl, C₁-C₆deuteroalkyl, —C₁-C₆alkyl-OH,        C₁-C₆haloalkyl, C₁-C₆alkoxy, C₃-C₆cycloalkyl,        C₂-C₉heterocycloalkyl, C₂-C₉heteroaryl, C₆-C₁₀aryl, —OR₁₁,        —N(R₁₁)₂, —CN, —C(═O)R₁₂, —C(═O)OR₁₁, —C(═O)N(R₁₁)₂,        —NR₁₁C(═O)R₁₂, —NR₁₁S(═O)₂R₁₂, —S(═O)₂R₁₂, and —S(═O)₂N(R₁₁)₂,        wherein C₃-C₆cycloalkyl, C₂-C₉heterocycloalkyl, C₂-C₉heteroaryl,        or C₆-C₁₀aryl are optionally substituted with 1, 2, or 3 groups        selected from halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy,        and C₁-C₆haloalkoxy;    -   R₉ and R₁₀ are independently selected from hydrogen, deuterium,        C₁-C₆alkyl, and C₁-C₆deuteroalkyl;    -   each R₁₁ is independently selected from hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆heteroalkyl, and phenyl, wherein phenyl is        optionally substituted with 1, 2, or 3 groups selected from        halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy,        C₁-C₆haloalkoxy, C₂-C₉heterocycloalkyl, C₂-C₉heteroaryl, —OR₁₄,        —N(R₁₄)₂, —C(═O)OR₁₄, and —C(═O)N(R₁₄)₂;    -   each R₁₂ is independently selected from C₁-C₆alkyl and        C₁-C₆heteroalkyl;    -   each R₁₄ is independently selected from hydrogen, C₁-C₆alkyl,        and C₁-C₆haloalkyl;    -   R₁₅ and R₁₆ are independently selected from hydrogen, deuterium,        halogen, C₁-C₆alkyl, C₁-C₆deuteroalkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆heteroalkyl, —OR₁₁, —N(R₁₁)₂, —CN, —C(═O)R₁₂,        —C(═O)OR₁₁, —C(═O)N(R₁₁)₂, —NR₁₁C(═O)R₁₂, —NR₁₁S(═O)₂R₁₂,        —S(═O)₂R₁₂, and —S(═O)₂N(R₁₁)₂;    -   R₁₈ is hydrogen, deuterium, halogen, C₁-C₆alkyl, or        C₁-C₆deuteroalkyl; and    -   n is 1, 2, 3, or 4.

In some embodiments is a compound of Formula (III), or apharmaceutically acceptable salt or solvate thereof, wherein Y is═C(R₁₅)— and Z is ═C(R₁₆)—. In some embodiments is a compound of Formula(III), or a pharmaceutically acceptable salt or solvate thereof, whereinY is ═C(R₁₅)—, Z is ═C(R₁₆), R₁₅ is hydrogen, and R₁₆ is hydrogen. Insome embodiments is a compound of Formula (III), or a pharmaceuticallyacceptable salt or solvate thereof, wherein Y is ═C(R₁₅)—, Z is ═C(R₁₆),R₁₅ is hydrogen, and R₁₆ is halogen. In some embodiments is a compoundof Formula (III), or a pharmaceutically acceptable salt or solvatethereof, wherein Y is ═C(R₁₅)—, Z is ═C(R₁₆), R₁₅ is halogen, and R₁₆ ishalogen. In some embodiments is a compound of Formula (III), or apharmaceutically acceptable salt or solvate thereof, wherein Y is═C(R₁₅)—, Z is ═C(R₁₆), R₁₅ is hydrogen, and R₁₆ is C₁-C₆alkyl. In someembodiments is a compound of Formula (III), or a pharmaceuticallyacceptable salt or solvate thereof, wherein Y is ═C(R₁₅)—, Z is ═C(R₁₆),R₁₅ is hydrogen, and R₁₆ is C₁-C₆haloalkyl.

In some embodiments is a compound of Formula (III), or apharmaceutically acceptable salt or solvate thereof, wherein Y is ═N—and Z is ═C(R₁₆)—. In some embodiments is a compound of Formula (III),or a pharmaceutically acceptable salt or solvate thereof, wherein Y is═N—, Z is ═C(R₁₆), and R₁₆ is hydrogen. In some embodiments is acompound of Formula (III), or a pharmaceutically acceptable salt orsolvate thereof, wherein Y is ═N—, Z is ═C(R₁₆), and R₁₆ is halogen. Insome embodiments is a compound of Formula (III), or a pharmaceuticallyacceptable salt or solvate thereof, wherein Y is ═N—, Z is ═C(R₁₆), andR₁₆ is C₁-C₆alkyl. In some embodiments is a compound of Formula (III),or a pharmaceutically acceptable salt or solvate thereof, wherein Y is═N—, Z is ═C(R₁₆), and R₁₆ is C₁-C₆haloalkyl.

In some embodiments is a compound of Formula (III), or apharmaceutically acceptable salt or solvate thereof, wherein Y is═C(R₁₅)— and Z is ═N—. In some embodiments is a compound of Formula(III), or a pharmaceutically acceptable salt or solvate thereof, whereinY is ═C(R₁₅)—, Z is ═N—, and R₁₅ is hydrogen. In some embodiments is acompound of Formula (III), or a pharmaceutically acceptable salt orsolvate thereof, wherein Y is ═C(R₁₅)—, Z is ═N—, and R₁₅ is halogen. Insome embodiments is a compound of Formula (III), or a pharmaceuticallyacceptable salt or solvate thereof, wherein Y is ═C(R₁₅)—, Z is ═N—, andR₁₅ is C₁-C₆alkyl. In some embodiments is a compound of Formula (III),or a pharmaceutically acceptable salt or solvate thereof, wherein Y is═C(R₁₅)—, Z is ═N—, and R₁₅ is C₁-C₆haloalkyl.

In some embodiments is a compound of Formula (III), or apharmaceutically acceptable salt or solvate thereof, wherein Y is ═N—and Z is ═N—.

In some embodiments is a compound of Formula (III), or apharmaceutically acceptable salt or solvate thereof, wherein R₇ and R₈are independently selected from hydrogen, halogen, C₁-C₆alkyl,C₁-C₆haloalkyl, and C₁-C₆alkoxy. In some embodiments is a compound ofFormula (III), or a pharmaceutically acceptable salt or solvate thereof,wherein R₇ and R₈ are each hydrogen. In some embodiments is a compoundof Formula (III), or a pharmaceutically acceptable salt or solvatethereof, wherein R₇ and R₈ are each halogen. In some embodiments is acompound of Formula (III), or a pharmaceutically acceptable salt orsolvate thereof, wherein R₇ and R₈ are each C₁-C₆alkyl. In someembodiments is a compound of Formula (III), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₇ is hydrogen and R₈ ishalogen. In some embodiments is a compound of Formula (III), or apharmaceutically acceptable salt or solvate thereof, wherein R₇ ishydrogen and R₈ is C₁-C₆alkyl. In some embodiments is a compound ofFormula (III), or a pharmaceutically acceptable salt or solvate thereof,wherein R₇ is hydrogen and R₈ is C₁-C₆haloalkyl. In some embodiments isa compound of Formula (III), or a pharmaceutically acceptable salt orsolvate thereof, wherein R₇ is hydrogen and R₈ is C₁-C₆alkoxy. In someembodiments is a compound of Formula (III), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₇ is hydrogen and R₈ is—CN. In some embodiments is a compound of Formula (III), or apharmaceutically acceptable salt or solvate thereof, wherein R₇ ishalogen and R₈ is hydrogen. In some embodiments is a compound of Formula(III), or a pharmaceutically acceptable salt or solvate thereof, whereinR₇ is C₁-C₆alkyl and R₈ is hydrogen. In some embodiments is a compoundof Formula (III), or a pharmaceutically acceptable salt or solvatethereof, wherein R₇ is C₁-C₆haloalkyl and R₈ is hydrogen. In someembodiments is a compound of Formula (III), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₇ is C₁-C₆alkoxy and R₈ ishydrogen. In some embodiments is a compound of Formula (III), or apharmaceutically acceptable salt or solvate thereof, wherein R₇ is —CNand R₈ is hydrogen.

In some embodiments is a compound of Formula (III), or apharmaceutically acceptable salt or solvate thereof, wherein X is —O—.In some embodiments is a compound of Formula (III), or apharmaceutically acceptable salt or solvate thereof, wherein X is —O—and n is 2. In some embodiments is a compound of Formula (III), or apharmaceutically acceptable salt or solvate thereof, wherein X is —O—, nis 2, and each R₁ and each R₂ are hydrogen. In some embodiments is acompound of Formula (III), or a pharmaceutically acceptable salt orsolvate thereof, wherein X is —O—, n is 2, each R₁ is hydrogen, and oneR₂ is hydrogen and one R₂ is C₁-C₆alkyl. In some embodiments is acompound of Formula (III), or a pharmaceutically acceptable salt orsolvate thereof, wherein X is —O— and n is 3. In some embodiments is acompound of Formula (III), or a pharmaceutically acceptable salt orsolvate thereof, wherein X is —O—, n is 3, and each R₁ and each R₂ arehydrogen. In some embodiments is a compound of Formula (III), or apharmaceutically acceptable salt or solvate thereof, wherein X is —O—, nis 3, one R₁ is C₁-C₆alkyl and one R₂ is C₁-C₆alkyl and the remaining R₁and R₂ are each hydrogen.

In some embodiments is a compound of Formula (III), or apharmaceutically acceptable salt or solvate thereof, wherein X is—C(R₉)(R₁₀)—. In some embodiments is a compound of Formula (III), or apharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—.In some embodiments is a compound of Formula (III), or apharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—and n is 1. In some embodiments is a compound of Formula (III), or apharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—,n is 1, and R₁ and R₂ are hydrogen. In some embodiments is a compound ofFormula (III), or a pharmaceutically acceptable salt or solvate thereof,wherein X is —CH₂— and n is 2. In some embodiments is a compound ofFormula (III), or a pharmaceutically acceptable salt or solvate thereof,wherein X is —CH₂—, n is 2, and each R₁ and each R₂ are hydrogen. Insome embodiments is a compound of Formula (III), or a pharmaceuticallyacceptable salt or solvate thereof, wherein X is —CH₂— and n is 3. Insome embodiments is a compound of Formula (III), or a pharmaceuticallyacceptable salt or solvate thereof, wherein X is —CH₂—, n is 3, and eachR₁ and each R₂ are hydrogen.

In some embodiments is a compound of Formula (III), or apharmaceutically acceptable salt or solvate thereof, wherein R₄ isselected from hydrogen and C₁-C₆alkyl. In some embodiments is a compoundof Formula (III), or a pharmaceutically acceptable salt or solvatethereof, wherein R₄ is hydrogen. In some embodiments is a compound ofFormula (III), or a pharmaceutically acceptable salt or solvate thereof,wherein R₄ is C₁-C₆alkyl.

In some embodiments is a compound of Formula (III), or apharmaceutically acceptable salt or solvate thereof, wherein R₅ isselected from hydrogen and C₁-C₆alkyl. In some embodiments is a compoundof Formula (III), or a pharmaceutically acceptable salt or solvatethereof, wherein R₅ is hydrogen. In some embodiments is a compound ofFormula (III), or a pharmaceutically acceptable salt or solvate thereof,wherein R₅ is C₁-C₆alkyl.

In some embodiments is a compound of Formula (III), or apharmaceutically acceptable salt or solvate thereof, wherein R₁₃ ishydrogen. In some embodiments is a compound of Formula (III), or apharmaceutically acceptable salt or solvate thereof, wherein R₅ and R₁₃together with the atoms to which they are attached are combined to forma 5- or 6-membered heterocycloalkyl ring or a 5- or 6-memberedheteroaryl ring, wherein the 5- or 6-membered heterocycloalkyl ring or5- or 6-membered heteroaryl ring is optionally substituted with 1, 2, or3 groups selected from halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy,and C₁-C₆haloalkoxy. In some embodiments is a compound of Formula (III),or a pharmaceutically acceptable salt or solvate thereof, wherein R₅ andR₁₃ together with the atoms to which they are attached are combined toform a 5- or 6-membered heterocycloalkyl ring, wherein the 5- or6-membered heterocycloalkyl ring is optionally substituted with 1, 2, or3 groups selected from halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy,and C₁-C₆haloalkoxy. In some embodiments is a compound of Formula (III),or a pharmaceutically acceptable salt or solvate thereof, wherein R₅ andR₁₃ together with the atoms to which they are attached are combined toform a 5- or 6-membered heteroaryl ring, wherein the 5- or 6-memberedheteroaryl ring is optionally substituted with 1, 2, or 3 groupsselected from halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, andC₁-C₆haloalkoxy.

In some embodiments is a compound of Formula (III), or apharmaceutically acceptable salt or solvate thereof, wherein R₄ ishydrogen and R₅ is C₁-C₆alkyl. In some embodiments is a compound ofFormula (III), or a pharmaceutically acceptable salt or solvate thereof,wherein R₄ and R₅ are hydrogen. In some embodiments is a compound ofFormula (III), or a pharmaceutically acceptable salt or solvate thereof,wherein R₄ and R₅ are C₁-C₆alkyl.

In some embodiments is a compound of Formula (III), or apharmaceutically acceptable salt or solvate thereof, wherein R₃ ishydrogen. In some embodiments is a compound of Formula (III), or apharmaceutically acceptable salt or solvate thereof, wherein R₃ isC₁-C₆alkyl.

In some embodiments is a compound of Formula (III), or apharmaceutically acceptable salt or solvate thereof, wherein R₆ ishydrogen. In some embodiments is a compound of Formula (III), or apharmaceutically acceptable salt or solvate thereof, wherein R₆ isC₁-C₆alkyl.

In some embodiments is a compound of Formula (III), or apharmaceutically acceptable salt or solvate thereof, wherein R₁₈ ishydrogen. In some embodiments is a compound of Formula (III), or apharmaceutically acceptable salt or solvate thereof, wherein R₁₈ isdeuterium. In some embodiments is a compound of Formula (III), or apharmaceutically acceptable salt or solvate thereof, wherein R₁₈ ishalogen. In some embodiments is a compound of Formula (III), or apharmaceutically acceptable salt or solvate thereof, wherein R₁₈ isC₁-C₆alkyl. In some embodiments is a compound of Formula (III), or apharmaceutically acceptable salt or solvate thereof, wherein R₁₈ isC₁-C₆deuteroalkyl.

In some embodiments, provided herein is a compound of Formula (IIIa), ora pharmaceutically acceptable salt or solvate thereof:

wherein:

-   -   X is —O— or —C(R₉)(R₁₀)—;    -   each R₁ is independently selected from hydrogen and C₁-C₆alkyl;    -   each R₂ is independently selected from hydrogen and C₁-C₆alkyl;    -   R₃ is hydrogen or C₁-C₆alkyl;    -   R₄ and R₅ are independently selected from hydrogen, C₁-C₆alkyl,        C₁-C₆heteroalkyl, C₃-C₆cycloalkyl, and C₂-C₉heterocycloalkyl;    -   R₆ is hydrogen or C₁-C₆alkyl;    -   R₇ and R₈ are independently selected from hydrogen, halogen,        C₁-C₆alkyl, —C₁-C₆alkyl-OH, C₁-C₆haloalkyl, C₁-C₆alkoxy,        C₃-C₆cycloalkyl, C₂-C₉heterocycloalkyl, C₂-C₉heteroaryl,        C₆-C₁₀aryl, —OR₁₁, —N(R₁₁)₂, —CN, —C(═O)R₁₂, —C(═O)OR₁₁,        —C(═O)N(R₁₁)₂, —NR₁₁C(═O)R₁₂, —NR₁₁S(═O)₂R₁₂, —S(═O)₂R₁₂, and        —S(═O)₂N(R₁₁)₂, wherein C₃-C₆cycloalkyl, C₂-C₉heterocycloalkyl,        C₂-C₉heteroaryl, or C₆-C₁₀aryl are optionally substituted with        1, 2, or 3 groups selected from halogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆alkoxy, and C₁-C₆haloalkoxy;    -   R₉ and R₁₀ are independently selected from hydrogen and        C₁-C₆alkyl;    -   each R₁₁ is independently selected from hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆heteroalkyl, and phenyl, wherein phenyl is        optionally substituted with 1, 2, or 3 groups selected from        halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy,        C₁-C₆haloalkoxy, C₂-C₉heterocycloalkyl, C₂-C₉heteroaryl, —OR₁₄,        —N(R₁₄)₂, —C(═O)OR₁₄, and —C(═O)N(R₁₄)₂;    -   each R₁₂ is independently selected from C₁-C₆alkyl and        C₁-C₆heteroalkyl;    -   each R₁₄ is independently selected from hydrogen, C₁-C₆alkyl,        and C₁-C₆haloalkyl;    -   R₁₅ and R₁₆ are independently selected from hydrogen, halogen,        C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆heteroalkyl,        —OR₁₁, —N(R₁₁)₂, —CN, —C(═O)R₁₂, —C(═O)OR₁₁, —C(═O)N(R₁₁)₂,        —NR₁₁C(═O)R₁₂, —NR₁₁S(═O)₂R₁₂, —S(═O)₂R₁₂, and —S(═O)₂N(R₁₁)₂;        and    -   n is 1, 2, 3, or 4.

In some embodiments is a compound of Formula (IIIa), or apharmaceutically acceptable salt or solvate thereof, wherein R₁₅ ishydrogen and R₁₆ is hydrogen. In some embodiments is a compound ofFormula (IIIa), or a pharmaceutically acceptable salt or solvatethereof, wherein R₁₅ is hydrogen and R₁₆ is halogen. In some embodimentsis a compound of Formula (IIIa), or a pharmaceutically acceptable saltor solvate thereof, wherein R₁₅ is halogen and R₁₆ is halogen. In someembodiments is a compound of Formula (IIIa), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₁₅ is hydrogen and R₁₆ isC₁-C₆alkyl. In some embodiments is a compound of Formula (IIIa), or apharmaceutically acceptable salt or solvate thereof, wherein R₁₅ ishydrogen and R₁₆ is C₁-C₆haloalkyl. In some embodiments is a compound ofFormula (IIIa), or a pharmaceutically acceptable salt or solvatethereof, wherein R₁₅ is halogen and R₁₆ is hydrogen.

In some embodiments is a compound of Formula (IIIa), or apharmaceutically acceptable salt or solvate thereof, wherein R₇ and R₈are independently selected from hydrogen, halogen, C₁-C₆alkyl,C₁-C₆haloalkyl, and C₁-C₆alkoxy. In some embodiments is a compound ofFormula (IIIa), or a pharmaceutically acceptable salt or solvatethereof, wherein R₇ and R₈ are each hydrogen. In some embodiments is acompound of Formula (IIIa), or a pharmaceutically acceptable salt orsolvate thereof, wherein R₇ and R₈ are each halogen. In some embodimentsis a compound of Formula (IIIa), or a pharmaceutically acceptable saltor solvate thereof, wherein R₇ and R₈ are each C₁-C₆alkyl. In someembodiments is a compound of Formula (IIIa), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₇ is hydrogen and R₈ ishalogen. In some embodiments is a compound of Formula (IIIa), or apharmaceutically acceptable salt or solvate thereof, wherein R₇ ishydrogen and R₈ is C₁-C₆alkyl. In some embodiments is a compound ofFormula (IIIa), or a pharmaceutically acceptable salt or solvatethereof, wherein R₇ is hydrogen and R₈ is C₁-C₆haloalkyl. In someembodiments is a compound of Formula (IIIa), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₇ is hydrogen and R₈ isC₁-C₆alkoxy. In some embodiments is a compound of Formula (IIIa), or apharmaceutically acceptable salt or solvate thereof, wherein R₇ ishydrogen and R₈ is —CN. In some embodiments is a compound of Formula(IIIa), or a pharmaceutically acceptable salt or solvate thereof,wherein R₇ is halogen and R₈ is hydrogen. In some embodiments is acompound of Formula (IIIa), or a pharmaceutically acceptable salt orsolvate thereof, wherein R₇ is C₁-C₆alkyl and R₈ is hydrogen. In someembodiments is a compound of Formula (IIIa), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₇ is C₁-C₆haloalkyl and R₈is hydrogen. In some embodiments is a compound of Formula (IIIa), or apharmaceutically acceptable salt or solvate thereof, wherein R₇ isC₁-C₆alkoxy and R₈ is hydrogen. In some embodiments is a compound ofFormula (IIIa), or a pharmaceutically acceptable salt or solvatethereof, wherein R₇ is —CN and R₈ is hydrogen.

In some embodiments is a compound of Formula (IIIa), or apharmaceutically acceptable salt or solvate thereof, wherein X is —O—.In some embodiments is a compound of Formula (IIIa), or apharmaceutically acceptable salt or solvate thereof, wherein X is —O—and n is 2. In some embodiments is a compound of Formula (IIIa), or apharmaceutically acceptable salt or solvate thereof, wherein X is —O—, nis 2, and each R₁ and each R₂ are hydrogen. In some embodiments is acompound of Formula (IIIa), or a pharmaceutically acceptable salt orsolvate thereof, wherein X is —O—, n is 2, each R₁ is hydrogen, and oneR₂ is hydrogen and one R₂ is C₁-C₆alkyl. In some embodiments is acompound of Formula (IIIa), or a pharmaceutically acceptable salt orsolvate thereof, wherein X is —O— and n is 3. In some embodiments is acompound of Formula (IIIa), or a pharmaceutically acceptable salt orsolvate thereof, wherein X is —O—, n is 3, and each R₁ and each R₂ arehydrogen. In some embodiments is a compound of Formula (IIIa), or apharmaceutically acceptable salt or solvate thereof, wherein X is —O—, nis 3, one R₁ is C₁-C₆alkyl and one R₂ is C₁-C₆alkyl and the remaining R₁and R₂ are each hydrogen.

In some embodiments is a compound of Formula (IIIa), or apharmaceutically acceptable salt or solvate thereof, wherein X is—C(R₉)(R₁₀)—. In some embodiments is a compound of Formula (IIIa), or apharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—.In some embodiments is a compound of Formula (IIIa), or apharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—and n is 1. In some embodiments is a compound of Formula (IIIa), or apharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—,n is 1, and R₁ and R₂ are hydrogen. In some embodiments is a compound ofFormula (IIIa), or a pharmaceutically acceptable salt or solvatethereof, wherein X is —CH₂— and n is 2. In some embodiments is acompound of Formula (IIIa), or a pharmaceutically acceptable salt orsolvate thereof, wherein X is —CH₂—, n is 2, and each R₁ and each R₂ arehydrogen. In some embodiments is a compound of Formula (IIIa), or apharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—and n is 3. In some embodiments is a compound of Formula (IIIa), or apharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—,n is 3, and each R₁ and each R₂ are hydrogen.

In some embodiments is a compound of Formula (IIIa), or apharmaceutically acceptable salt or solvate thereof, wherein R₄ and R₅are independently selected from hydrogen and C₁-C₆alkyl. In someembodiments is a compound of Formula (IIIa), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₄ is hydrogen and R₅ isC₁-C₆alkyl. In some embodiments is a compound of Formula (IIIa), or apharmaceutically acceptable salt or solvate thereof, wherein R₄ and R₅are hydrogen. In some embodiments is a compound of Formula (IIIa), or apharmaceutically acceptable salt or solvate thereof, wherein R₄ and R₅are C₁-C₆alkyl.

In some embodiments is a compound of Formula (IIIa), or apharmaceutically acceptable salt or solvate thereof, wherein R₃ ishydrogen. In some embodiments is a compound of Formula (IIIa), or apharmaceutically acceptable salt or solvate thereof, wherein R₃ isC₁-C₆alkyl.

In some embodiments is a compound of Formula (IIIa), or apharmaceutically acceptable salt or solvate thereof, wherein R₆ ishydrogen. In some embodiments is a compound of Formula (IIIa), or apharmaceutically acceptable salt or solvate thereof, wherein R₆ isC₁-C₆alkyl.

In some embodiments, provided herein is a compound of Formula (IIIb), ora pharmaceutically acceptable salt or solvate thereof:

wherein:

-   -   X is —O— or —C(R₉)(R₁₀)—;    -   each R₁ is independently selected from hydrogen and C₁-C₆alkyl;    -   each R₂ is independently selected from hydrogen and C₁-C₆alkyl;    -   R₃ is hydrogen or C₁-C₆alkyl;    -   R₄ and R₅ are independently selected from hydrogen, C₁-C₆alkyl,        C₁-C₆heteroalkyl, C₃-C₆cycloalkyl, and C₂-C₉heterocycloalkyl;    -   R₆ is hydrogen or C₁-C₆alkyl;    -   R₇ and R₈ are independently selected from hydrogen, halogen,        C₁-C₆alkyl, —C₁-C₆alkyl-OH, C₁-C₆haloalkyl, C₁-C₆alkoxy,        C₃-C₆cycloalkyl, C₂-C₉heterocycloalkyl, C₂-C₉heteroaryl,        C₆-C₁₀aryl, —OR₁₁, —N(R₁₁)₂, —CN, —C(═O)R₁₂, —C(═O)OR₁₁,        —C(═O)N(R₁₁)₂, —NR₁₁C(═O)R₁₂, —NR₁₁S(═O)₂R₁₂, —S(═O)₂R₁₂, and        —S(═O)₂N(R₁₁)₂, wherein C₃-C₆cycloalkyl, C₂-C₉heterocycloalkyl,        C₂-C₉heteroaryl, or C₆-C₁₀aryl are optionally substituted with        1, 2, or 3 groups selected from halogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆alkoxy, and C₁-C₆haloalkoxy;    -   R₉ and R₁₀ are independently selected from hydrogen and        C₁-C₆alkyl;    -   each R₁₁ is independently selected from hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆heteroalkyl, and phenyl, wherein phenyl is        optionally substituted with 1, 2, or 3 groups selected from        halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy,        C₁-C₆haloalkoxy, C₂-C₉heterocycloalkyl, C₂-C₉heteroaryl, —OR₁₄,        —N(R₁₄)₂, —C(═O)OR₁₄, and —C(═O)N(R₁₄)₂;    -   each R₁₂ is independently selected from C₁-C₆alkyl and        C₁-C₆heteroalkyl;    -   each R₁₄ is independently selected from hydrogen, C₁-C₆alkyl,        and C₁-C₆haloalkyl;    -   R₁₆ is selected from hydrogen, halogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆heteroalkyl, —OR₁₁, —N(R₁₁)₂,        —CN, —C(═O)R₁₂, —C(═O)OR₁₁, —C(═O)N(R₁₁)₂, —NR₁₁C(═O)R₁₂,        —NR₁₁S(═O)₂R₁₂, —S(═O)₂R₁₂, and —S(═O)₂N(R₁₁)₂; and    -   n is 1, 2, 3, or 4.

In some embodiments is a compound of Formula (IIIb), or apharmaceutically acceptable salt or solvate thereof, wherein R₁₆ ishydrogen. In some embodiments is a compound of Formula (IIIb), or apharmaceutically acceptable salt or solvate thereof, wherein R₁₆ ishalogen. In some embodiments is a compound of Formula (IIIb), or apharmaceutically acceptable salt or solvate thereof, wherein R₁₆ isC₁-C₆alkyl. In some embodiments is a compound of Formula (IIIb), or apharmaceutically acceptable salt or solvate thereof, wherein R₁₆ isC₁-C₆haloalkyl.

In some embodiments is a compound of Formula (IIIb), or apharmaceutically acceptable salt or solvate thereof, wherein R₇ and R₈are independently selected from hydrogen, halogen, C₁-C₆alkyl,C₁-C₆haloalkyl, and C₁-C₆alkoxy. In some embodiments is a compound ofFormula (IIIb), or a pharmaceutically acceptable salt or solvatethereof, wherein R₇ and R₈ are each hydrogen. In some embodiments is acompound of Formula (IIIb), or a pharmaceutically acceptable salt orsolvate thereof, wherein R₇ and R₈ are each halogen. In some embodimentsis a compound of Formula (IIIb), or a pharmaceutically acceptable saltor solvate thereof, wherein R₇ and R₈ are each C₁-C₆alkyl. In someembodiments is a compound of Formula (IIIb), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₇ is hydrogen and R₈ ishalogen. In some embodiments is a compound of Formula (IIIb), or apharmaceutically acceptable salt or solvate thereof, wherein R₇ ishydrogen and R₈ is C₁-C₆alkyl. In some embodiments is a compound ofFormula (IIIb), or a pharmaceutically acceptable salt or solvatethereof, wherein R₇ is hydrogen and R₈ is C₁-C₆haloalkyl. In someembodiments is a compound of Formula (IIIb), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₇ is hydrogen and R₈ isC₁-C₆alkoxy. In some embodiments is a compound of Formula (IIIb), or apharmaceutically acceptable salt or solvate thereof, wherein R₇ ishydrogen and R₈ is —CN. In some embodiments is a compound of Formula(IIIb), or a pharmaceutically acceptable salt or solvate thereof,wherein R₇ is halogen and R₈ is hydrogen. In some embodiments is acompound of Formula (IIIb), or a pharmaceutically acceptable salt orsolvate thereof, wherein R₇ is C₁-C₆alkyl and R₈ is hydrogen. In someembodiments is a compound of Formula (IIIb), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₇ is C₁-C₆haloalkyl and R₈is hydrogen. In some embodiments is a compound of Formula (IIIb), or apharmaceutically acceptable salt or solvate thereof, wherein R₇ isC₁-C₆alkoxy and R₈ is hydrogen. In some embodiments is a compound ofFormula (IIIb), or a pharmaceutically acceptable salt or solvatethereof, wherein R₇ is —CN and R₈ is hydrogen.

In some embodiments is a compound of Formula (IIIb), or apharmaceutically acceptable salt or solvate thereof, wherein X is —O—.In some embodiments is a compound of Formula (IIIb), or apharmaceutically acceptable salt or solvate thereof, wherein X is —O—and n is 2. In some embodiments is a compound of Formula (IIIb), or apharmaceutically acceptable salt or solvate thereof, wherein X is —O—, nis 2, and each R₁ and each R₂ are hydrogen. In some embodiments is acompound of Formula (IIIb), or a pharmaceutically acceptable salt orsolvate thereof, wherein X is —O—, n is 2, each R₁ is hydrogen, and oneR₂ is hydrogen and one R₂ is C₁-C₆alkyl. In some embodiments is acompound of Formula (IIIb), or a pharmaceutically acceptable salt orsolvate thereof, wherein X is —O— and n is 3. In some embodiments is acompound of Formula (IIIb), or a pharmaceutically acceptable salt orsolvate thereof, wherein X is —O—, n is 3, and each R₁ and each R₂ arehydrogen. In some embodiments is a compound of Formula (IIIb), or apharmaceutically acceptable salt or solvate thereof, wherein X is —O—, nis 3, one R₁ is C₁-C₆alkyl and one R₂ is C₁-C₆alkyl and the remaining R₁and R₂ are each hydrogen.

In some embodiments is a compound of Formula (IIIb), or apharmaceutically acceptable salt or solvate thereof, wherein X is—C(R₉)(R₁₀)—. In some embodiments is a compound of Formula (IIIb), or apharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—.In some embodiments is a compound of Formula (IIIb), or apharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—and n is 1. In some embodiments is a compound of Formula (IIIb), or apharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—,n is 1, and R₁ and R₂ are hydrogen. In some embodiments is a compound ofFormula (IIIb), or a pharmaceutically acceptable salt or solvatethereof, wherein X is —CH₂— and n is 2. In some embodiments is acompound of Formula (IIIb), or a pharmaceutically acceptable salt orsolvate thereof, wherein X is —CH₂—, n is 2, and each R₁ and each R₂ arehydrogen. In some embodiments is a compound of Formula (IIIb), or apharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—and n is 3. In some embodiments is a compound of Formula (IIIb), or apharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—,n is 3, and each R₁ and each R₂ are hydrogen.

In some embodiments is a compound of Formula (IIIb), or apharmaceutically acceptable salt or solvate thereof, wherein R₄ and R₅are independently selected from hydrogen and C₁-C₆alkyl. In someembodiments is a compound of Formula (IIIb), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₄ is hydrogen and R₅ isC₁-C₆alkyl. In some embodiments is a compound of Formula (IIIb), or apharmaceutically acceptable salt or solvate thereof, wherein R₄ and R₅are hydrogen. In some embodiments is a compound of Formula (IIIb), or apharmaceutically acceptable salt or solvate thereof, wherein R₄ and R₅are C₁-C₆alkyl.

In some embodiments is a compound of Formula (IIIb), or apharmaceutically acceptable salt or solvate thereof, wherein R₃ ishydrogen. In some embodiments is a compound of Formula (IIIb), or apharmaceutically acceptable salt or solvate thereof, wherein R₃ isC₁-C₆alkyl.

In some embodiments is a compound of Formula (IIIb), or apharmaceutically acceptable salt or solvate thereof, wherein R₆ ishydrogen. In some embodiments is a compound of Formula (IIIb), or apharmaceutically acceptable salt or solvate thereof, wherein R₆ isC₁-C₆alkyl.

In some embodiments, provided herein is a compound of Formula (IIIc), ora pharmaceutically acceptable salt or solvate thereof:

wherein:

-   -   X is —O— or —C(R₉)(R₁₀)—;    -   each R₁ is independently selected from hydrogen and C₁-C₆alkyl;    -   each R₂ is independently selected from hydrogen and C₁-C₆alkyl;    -   R₃ is hydrogen or C₁-C₆alkyl;    -   R₄ and R₅ are independently selected from hydrogen, C₁-C₆alkyl,        C₁-C₆heteroalkyl, C₃-C₆cycloalkyl, and C₂-C₉heterocycloalkyl;    -   R₆ is hydrogen or C₁-C₆alkyl;    -   R₇ and R₈ are independently selected from hydrogen, halogen,        C₁-C₆alkyl, —C₁-C₆alkyl-OH, C₁-C₆haloalkyl, C₁-C₆alkoxy,        C₃-C₆cycloalkyl, C₂-C₉heterocycloalkyl, C₂-C₉heteroaryl,        C₆-C₁₀aryl, —OR₁₁, —N(R₁₁)₂, —CN, —C(═O)R₁₂, —C(═O)OR₁₁,        —C(═O)N(R₁₁)₂, —NR₁₁C(═O)R₁₂, —NR₁₁S(═O)₂R₁₂, —S(═O)₂R₁₂, and        —S(═O)₂N(R₁₁)₂, wherein C₃-C₆cycloalkyl, C₂-C₉heterocycloalkyl,        C₂-C₉heteroaryl, or C₆-C₁₀aryl are optionally substituted with        1, 2, or 3 groups selected from halogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆alkoxy, and C₁-C₆haloalkoxy;    -   R₉ and R₁₀ are independently selected from hydrogen and        C₁-C₆alkyl;    -   each R₁₁ is independently selected from hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆heteroalkyl, and phenyl, wherein phenyl is        optionally substituted with 1, 2, or 3 groups selected from        halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy,        C₁-C₆haloalkoxy, C₂-C₉heterocycloalkyl, C₂-C₉heteroaryl, —OR₁₄,        —N(R₁₄)₂, —C(═O)OR₁₄, and —C(═O)N(R₁₄)₂;    -   each R₁₂ is independently selected from C₁-C₆alkyl and        C₁-C₆heteroalkyl;    -   each R₁₄ is independently selected from hydrogen, C₁-C₆alkyl,        and C₁-C₆haloalkyl;    -   R₁₅ is selected from hydrogen, halogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆heteroalkyl, —OR₁₁, —N(R₁₁)₂,        —CN, —C(═O)R₁₂, —C(═O)OR₁₁, —C(═O)N(R₁₁)₂, —NR₁₁C(═O)R₁₂,        —NR₁₁S(═O)₂R₁₂, —S(═O)₂R₁₂, and —S(═O)₂N(R₁₁)₂; and    -   n is 1, 2, 3, or 4.

In some embodiments is a compound of Formula (IIIc), or apharmaceutically acceptable salt or solvate thereof, wherein R₁₅ ishydrogen. In some embodiments is a compound of Formula (IIIc), or apharmaceutically acceptable salt or solvate thereof, wherein R₁₅ ishalogen. In some embodiments is a compound of Formula (IIIc), or apharmaceutically acceptable salt or solvate thereof, wherein R₁₅ isC₁-C₆alkyl. In some embodiments is a compound of Formula (IIIc), or apharmaceutically acceptable salt or solvate thereof, wherein R₁₅ isC₁-C₆haloalkyl.

In some embodiments is a compound of Formula (IIIc), or apharmaceutically acceptable salt or solvate thereof, wherein R₇ and R₈are independently selected from hydrogen, halogen, C₁-C₆alkyl,C₁-C₆haloalkyl, and C₁-C₆alkoxy. In some embodiments is a compound ofFormula (IIIc), or a pharmaceutically acceptable salt or solvatethereof, wherein R₇ and R₈ are each hydrogen. In some embodiments is acompound of Formula (IIIc), or a pharmaceutically acceptable salt orsolvate thereof, wherein R₇ and R₈ are each halogen. In some embodimentsis a compound of Formula (IIIc), or a pharmaceutically acceptable saltor solvate thereof, wherein R₇ and R₈ are each C₁-C₆alkyl. In someembodiments is a compound of Formula (IIIc), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₇ is hydrogen and R₈ ishalogen. In some embodiments is a compound of Formula (IIIc), or apharmaceutically acceptable salt or solvate thereof, wherein R₇ ishydrogen and R₈ is C₁-C₆alkyl. In some embodiments is a compound ofFormula (IIIc), or a pharmaceutically acceptable salt or solvatethereof, wherein R₇ is hydrogen and R₈ is C₁-C₆haloalkyl. In someembodiments is a compound of Formula (IIIc), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₇ is hydrogen and R₈ isC₁-C₆alkoxy. In some embodiments is a compound of Formula (IIIc), or apharmaceutically acceptable salt or solvate thereof, wherein R₇ ishydrogen and R₈ is —CN. In some embodiments is a compound of Formula(IIIc), or a pharmaceutically acceptable salt or solvate thereof,wherein R₇ is halogen and R₈ is hydrogen. In some embodiments is acompound of Formula (IIIc), or a pharmaceutically acceptable salt orsolvate thereof, wherein R₇ is C₁-C₆alkyl and R₈ is hydrogen. In someembodiments is a compound of Formula (IIIc), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₇ is C₁-C₆haloalkyl and R₈is hydrogen. In some embodiments is a compound of Formula (IIIc), or apharmaceutically acceptable salt or solvate thereof, wherein R₇ isC₁-C₆alkoxy and R₈ is hydrogen. In some embodiments is a compound ofFormula (IIIc), or a pharmaceutically acceptable salt or solvatethereof, wherein R₇ is —CN and R₈ is hydrogen.

In some embodiments is a compound of Formula (IIIc), or apharmaceutically acceptable salt or solvate thereof, wherein X is —O—.In some embodiments is a compound of Formula (IIIc), or apharmaceutically acceptable salt or solvate thereof, wherein X is —O—and n is 2. In some embodiments is a compound of Formula (IIIc), or apharmaceutically acceptable salt or solvate thereof, wherein X is —O—, nis 2, and each R₁ and each R₂ are hydrogen. In some embodiments is acompound of Formula (IIIc), or a pharmaceutically acceptable salt orsolvate thereof, wherein X is —O—, n is 2, each R₁ is hydrogen, and oneR₂ is hydrogen and one R₂ is C₁-C₆alkyl. In some embodiments is acompound of Formula (IIIc), or a pharmaceutically acceptable salt orsolvate thereof, wherein X is —O— and n is 3. In some embodiments is acompound of Formula (IIIc), or a pharmaceutically acceptable salt orsolvate thereof, wherein X is —O—, n is 3, and each R₁ and each R₂ arehydrogen. In some embodiments is a compound of Formula (IIIc), or apharmaceutically acceptable salt or solvate thereof, wherein X is —O—, nis 3, one R₁ is C₁-C₆alkyl and one R₂ is C₁-C₆alkyl and the remaining R₁and R₂ are each hydrogen.

In some embodiments is a compound of Formula (IIIc), or apharmaceutically acceptable salt or solvate thereof, wherein X is—C(R₉)(R₁₀)—. In some embodiments is a compound of Formula (IIIc), or apharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—.In some embodiments is a compound of Formula (IIIc), or apharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—and n is 1. In some embodiments is a compound of Formula (IIIc), or apharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—,n is 1, and R₁ and R₂ are hydrogen. In some embodiments is a compound ofFormula (IIIc), or a pharmaceutically acceptable salt or solvatethereof, wherein X is —CH₂— and n is 2. In some embodiments is acompound of Formula (IIIc), or a pharmaceutically acceptable salt orsolvate thereof, wherein X is —CH₂—, n is 2, and each R₁ and each R₂ arehydrogen. In some embodiments is a compound of Formula (IIIc), or apharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—and n is 3. In some embodiments is a compound of Formula (IIIc), or apharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—,n is 3, and each R₁ and each R₂ are hydrogen.

In some embodiments is a compound of Formula (IIIc), or apharmaceutically acceptable salt or solvate thereof, wherein R₄ and R₅are independently selected from hydrogen and C₁-C₆alkyl. In someembodiments is a compound of Formula (IIIc), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₄ is hydrogen and R₅ isC₁-C₆alkyl. In some embodiments is a compound of Formula (IIIc), or apharmaceutically acceptable salt or solvate thereof, wherein R₄ and R₅are hydrogen. In some embodiments is a compound of Formula (IIIc), or apharmaceutically acceptable salt or solvate thereof, wherein R₄ and R₅are C₁-C₆alkyl.

In some embodiments is a compound of Formula (IIIc), or apharmaceutically acceptable salt or solvate thereof, wherein R₃ ishydrogen. In some embodiments is a compound of Formula (IIIc), or apharmaceutically acceptable salt or solvate thereof, wherein R₃ isC₁-C₆alkyl.

In some embodiments is a compound of Formula (IIIc), or apharmaceutically acceptable salt or solvate thereof, wherein R₆ ishydrogen. In some embodiments is a compound of Formula (IIIc), or apharmaceutically acceptable salt or solvate thereof, wherein R₆ isC₁-C₆alkyl.

In some embodiments, provided herein is a compound of Formula (IIId), ora pharmaceutically acceptable salt or solvate thereof:

wherein:

-   -   X is —O— or —C(R₉)(R₁₀)—;    -   each R₁ is independently selected from hydrogen and C₁-C₆alkyl;    -   each R₂ is independently selected from hydrogen and C₁-C₆alkyl;    -   R₃ is hydrogen or C₁-C₆alkyl;    -   R₄ and R₅ are independently selected from hydrogen, C₁-C₆alkyl,        C₁-C₆heteroalkyl, C₃-C₆cycloalkyl, and C₂-C₉heterocycloalkyl;    -   R₆ is hydrogen or C₁-C₆alkyl;    -   R₇ and R₈ are independently selected from hydrogen, halogen,        C₁-C₆alkyl, —C₁-C₆alkyl-OH, C₁-C₆haloalkyl, C₁-C₆alkoxy,        C₃-C₆cycloalkyl, C₂-C₉heterocycloalkyl, C₂-C₉heteroaryl,        C₆-C₁₀aryl, —OR₁₁, —N(R₁₁)₂, —CN, —C(═O)R₁₂, —C(═O)OR₁₁,        —C(═O)N(R₁₁)₂, —NR₁₁C(═O)R₁₂, —NR₁₁S(═O)₂R₁₂, —S(═O)₂R₁₂, and        —S(═O)₂N(R₁₁)₂, wherein C₃-C₆cycloalkyl, C₂-C₉heterocycloalkyl,        C₂-C₉heteroaryl, or C₆-C₁₀aryl are optionally substituted with        1, 2, or 3 groups selected from halogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆alkoxy, and C₁-C₆haloalkoxy;    -   R₉ and R₁₀ are independently selected from hydrogen and        C₁-C₆alkyl;    -   each R₁₁ is independently selected from hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆heteroalkyl, and phenyl, wherein phenyl is        optionally substituted with 1, 2, or 3 groups selected from        halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy,        C₁-C₆haloalkoxy, C₂-C₉heterocycloalkyl, C₂-C₉heteroaryl, —OR₁₄,        —N(R₁₄)₂, —C(═O)OR₁₄, and —C(═O)N(R₁₄)₂;    -   each R₁₂ is independently selected from C₁-C₆alkyl and        C₁-C₆heteroalkyl;    -   each R₁₄ is independently selected from hydrogen, C₁-C₆alkyl,        and C₁-C₆haloalkyl; and    -   n is 1, 2, 3, or 4.

In some embodiments is a compound of Formula (IIId), or apharmaceutically acceptable salt or solvate thereof, wherein R₇ and R₈are independently selected from hydrogen, halogen, C₁-C₆alkyl,C₁-C₆haloalkyl, and C₁-C₆alkoxy. In some embodiments is a compound ofFormula (IIId), or a pharmaceutically acceptable salt or solvatethereof, wherein R₇ and R₈ are each hydrogen. In some embodiments is acompound of Formula (IIId), or a pharmaceutically acceptable salt orsolvate thereof, wherein R₇ and R₈ are each halogen. In some embodimentsis a compound of Formula (IIId), or a pharmaceutically acceptable saltor solvate thereof, wherein R₇ and R₈ are each C₁-C₆alkyl. In someembodiments is a compound of Formula (IIId), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₇ is hydrogen and R₈ ishalogen. In some embodiments is a compound of Formula (IIId), or apharmaceutically acceptable salt or solvate thereof, wherein R₇ ishydrogen and R₈ is C₁-C₆alkyl. In some embodiments is a compound ofFormula (IIId), or a pharmaceutically acceptable salt or solvatethereof, wherein R₇ is hydrogen and R₈ is C₁-C₆haloalkyl. In someembodiments is a compound of Formula (IIId), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₇ is hydrogen and R₈ isC₁-C₆alkoxy. In some embodiments is a compound of Formula (IIId), or apharmaceutically acceptable salt or solvate thereof, wherein R₇ ishydrogen and R₈ is —CN. In some embodiments is a compound of Formula(IIId), or a pharmaceutically acceptable salt or solvate thereof,wherein R₇ is halogen and R₈ is hydrogen. In some embodiments is acompound of Formula (IIId), or a pharmaceutically acceptable salt orsolvate thereof, wherein R₇ is C₁-C₆alkyl and R₈ is hydrogen. In someembodiments is a compound of Formula (IIId), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₇ is C₁-C₆haloalkyl and R₈is hydrogen. In some embodiments is a compound of Formula (IIId), or apharmaceutically acceptable salt or solvate thereof, wherein R₇ isC₁-C₆alkoxy and R₈ is hydrogen. In some embodiments is a compound ofFormula (IIId), or a pharmaceutically acceptable salt or solvatethereof, wherein R₇ is —CN and R₈ is hydrogen.

In some embodiments is a compound of Formula (IIId), or apharmaceutically acceptable salt or solvate thereof, wherein X is —O—.In some embodiments is a compound of Formula (IIId), or apharmaceutically acceptable salt or solvate thereof, wherein X is —O—and n is 2. In some embodiments is a compound of Formula (IIId), or apharmaceutically acceptable salt or solvate thereof, wherein X is —O—, nis 2, and each R₁ and each R₂ are hydrogen. In some embodiments is acompound of Formula (IIId), or a pharmaceutically acceptable salt orsolvate thereof, wherein X is —O—, n is 2, each R₁ is hydrogen, and oneR₂ is hydrogen and one R₂ is C₁-C₆alkyl. In some embodiments is acompound of Formula (IIId), or a pharmaceutically acceptable salt orsolvate thereof, wherein X is —O— and n is 3. In some embodiments is acompound of Formula (IIId), or a pharmaceutically acceptable salt orsolvate thereof, wherein X is —O—, n is 3, and each R₁ and each R₂ arehydrogen. In some embodiments is a compound of Formula (IIId), or apharmaceutically acceptable salt or solvate thereof, wherein X is —O—, nis 3, one R₁ is C₁-C₆alkyl and one R₂ is C₁-C₆alkyl and the remaining R₁and R₂ are each hydrogen.

In some embodiments is a compound of Formula (IIId), or apharmaceutically acceptable salt or solvate thereof, wherein X is—C(R₉)(R₁₀)—. In some embodiments is a compound of Formula (IIId), or apharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—.In some embodiments is a compound of Formula (IIId), or apharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—and n is 1. In some embodiments is a compound of Formula (IIId), or apharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—,n is 1, and R₁ and R₂ are hydrogen. In some embodiments is a compound ofFormula (IIId), or a pharmaceutically acceptable salt or solvatethereof, wherein X is —CH₂— and n is 2. In some embodiments is acompound of Formula (IIId), or a pharmaceutically acceptable salt orsolvate thereof, wherein X is —CH₂—, n is 2, and each R₁ and each R₂ arehydrogen. In some embodiments is a compound of Formula (IIId), or apharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—and n is 3. In some embodiments is a compound of Formula (IIId), or apharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—,n is 3, and each R₁ and each R₂ are hydrogen.

In some embodiments is a compound of Formula (IIId), or apharmaceutically acceptable salt or solvate thereof, wherein R₄ and R₅are independently selected from hydrogen and C₁-C₆alkyl. In someembodiments is a compound of Formula (IIId), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₄ is hydrogen and R₅ isC₁-C₆alkyl. In some embodiments is a compound of Formula (IIId), or apharmaceutically acceptable salt or solvate thereof, wherein R₄ and R₅are hydrogen. In some embodiments is a compound of Formula (IIId), or apharmaceutically acceptable salt or solvate thereof, wherein R₄ and R₅are C₁-C₆alkyl.

In some embodiments is a compound of Formula (IIId), or apharmaceutically acceptable salt or solvate thereof, wherein R₃ ishydrogen. In some embodiments is a compound of Formula (IIId), or apharmaceutically acceptable salt or solvate thereof, wherein R₃ isC₁-C₆alkyl.

In some embodiments is a compound of Formula (IIId), or apharmaceutically acceptable salt or solvate thereof, wherein R₆ ishydrogen. In some embodiments is a compound of Formula (IIId), or apharmaceutically acceptable salt or solvate thereof, wherein R₆ isC₁-C₆alkyl.

In some embodiments, provided herein is a compound of Formula (IV), or apharmaceutically acceptable salt or solvate thereof:

wherein:

-   -   X is —O— or —C(R₉)(R₁₀)—;    -   Y is ═N— or ═C(R₁₅)—;    -   Z is ═N— or ═C(R₁₆)—;    -   each R₁ is independently selected from hydrogen, deuterium,        C₁-C₆alkyl, and C₁-C₆deuteroalkyl;    -   each R₂ is independently selected from hydrogen, deuterium,        C₁-C₆alkyl, and C₁-C₆deuteroalkyl;    -   R₃ is hydrogen or C₁-C₆alkyl;    -   R₄ is selected from hydrogen, deuterium, C₁-C₆alkyl,        C₁-C₆deuteroalkyl, C₁-C₆heteroalkyl, C₃-C₆cycloalkyl, and        C₂-C₉heterocycloalkyl;    -   R₅ is selected from hydrogen, deuterium, C₁-C₆alkyl,        C₁-C₆deuteroalkyl, C₁-C₆heteroalkyl, C₃-C₆cycloalkyl, and        C₂-C₉heterocycloalkyl;    -   R₁₃ is hydrogen, deuterium, C₁-C₆alkyl, or C₁-C₆deuteroalkyl; or        R₅ and R₁₃ together with the atoms to which they are attached        are combined to form a 5- or 6-membered heterocycloalkyl ring or        a 5- or 6-membered heteroaryl ring, wherein the 5- or 6-membered        heterocycloalkyl ring or 5- or 6-membered heteroaryl ring is        optionally substituted with 1, 2, or 3 groups selected from        halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, and        C₁-C₆haloalkoxy;    -   R₆ is hydrogen or C₁-C₆alkyl;    -   R₇ and R₈ are independently selected from hydrogen, deuterium,        halogen, C₁-C₆alkyl, C₁-C₆deuteroalkyl, —C₁-C₆alkyl-OH,        C₁-C₆haloalkyl, C₁-C₆alkoxy, C₃-C₆cycloalkyl,        C₂-C₉heterocycloalkyl, C₂-C₉heteroaryl, C₆-C₁₀aryl, —OR₁₁,        —N(R₁₁)₂, —CN, —C(═O)R₁₂, —C(═O)OR₁₁, —C(═O)N(R₁₁)₂,        —NR₁₁C(═O)R₁₂, —NR₁₁S(═O)₂R₁₂, —S(═O)₂R₁₂, and —S(═O)₂N(R₁₁)₂,        wherein C₃-C₆cycloalkyl, C₂-C₉heterocycloalkyl, C₂-C₉heteroaryl,        or C₆-C₁₀aryl are optionally substituted with 1, 2, or 3 groups        selected from halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy,        and C₁-C₆haloalkoxy;    -   R₉ and R₁₀ are independently selected from hydrogen, deuterium,        C₁-C₆alkyl, and C₁-C₆deuteroalkyl;    -   each R₁₁ is independently selected from hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆heteroalkyl, and phenyl, wherein phenyl is        optionally substituted with 1, 2, or 3 groups selected from        halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy,        C₁-C₆haloalkoxy, C₂-C₉heterocycloalkyl, C₂-C₉heteroaryl, —OR₁₄,        —N(R₁₄)₂, —C(═O)OR₁₄, and —C(═O)N(R₁₄)₂;    -   each R₁₂ is independently selected from C₁-C₆alkyl and        C₁-C₆heteroalkyl;    -   each R₁₄ is independently selected from hydrogen, C₁-C₆alkyl,        and C₁-C₆haloalkyl;    -   R₁₅ and R₁₆ are independently selected from hydrogen, deuterium,        halogen, C₁-C₆alkyl, C₁-C₆deuteroalkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆heteroalkyl, —OR₁₁, —N(R₁₁)₂, —CN, —C(═O)R₁₂,        —C(═O)OR₁₁, —C(═O)N(R₁₁)₂, —NR₁₁C(═O)R₁₂, —NR₁₁S(═O)₂R₁₂,        —S(═O)₂R₁₂, and —S(═O)₂N(R₁₁)₂;    -   R₁₈ is hydrogen, deuterium, halogen, C₁-C₆alkyl, or        C₁-C₆deuteroalkyl; and    -   n is 1, 2, 3, or 4.

In some embodiments is a compound of Formula (IV), or a pharmaceuticallyacceptable salt or solvate thereof, wherein Y is ═C(R₁₅)— and Z is═C(R₁₆)—. In some embodiments is a compound of Formula (IV), or apharmaceutically acceptable salt or solvate thereof, wherein Y is═C(R₁₅)—, Z is ═C(R₁₆), R₁₅ is hydrogen, and R₁₆ is hydrogen. In someembodiments is a compound of Formula (IV), or a pharmaceuticallyacceptable salt or solvate thereof, wherein Y is ═C(R₁₅)—, Z is ═C(R₁₆),R₁₅ is hydrogen, and R₁₆ is halogen. In some embodiments is a compoundof Formula (IV), or a pharmaceutically acceptable salt or solvatethereof, wherein Y is ═C(R₁₅)—, Z is ═C(R₁₆), R₁₅ is halogen, and R₁₆ ishalogen. In some embodiments is a compound of Formula (IV), or apharmaceutically acceptable salt or solvate thereof, wherein Y is═C(R₁₅)—, Z is ═C(R₁₆), R₁₅ is hydrogen, and R₁₆ is C₁-C₆alkyl. In someembodiments is a compound of Formula (IV), or a pharmaceuticallyacceptable salt or solvate thereof, wherein Y is ═C(R₁₅)—, Z is ═C(R₁₆),R₁₅ is hydrogen, and R₁₆ is C₁-C₆haloalkyl.

In some embodiments is a compound of Formula (IV), or a pharmaceuticallyacceptable salt or solvate thereof, wherein Y is ═N— and Z is ═C(R₁₆)—.In some embodiments is a compound of Formula (IV), or a pharmaceuticallyacceptable salt or solvate thereof, wherein Y is ═N—, Z is ═C(R₁₆), andR₁₆ is hydrogen. In some embodiments is a compound of Formula (IV), or apharmaceutically acceptable salt or solvate thereof, wherein Y is ═N—, Zis ═C(R₁₆), and R₁₆ is halogen. In some embodiments is a compound ofFormula (IV), or a pharmaceutically acceptable salt or solvate thereof,wherein Y is ═N—, Z is ═C(R₁₆), and R₁₆ is C₁-C₆alkyl. In someembodiments is a compound of Formula (IV), or a pharmaceuticallyacceptable salt or solvate thereof, wherein Y is ═N—, Z is ═C(R₁₆), andR₁₆ is C₁-C₆haloalkyl.

In some embodiments is a compound of Formula (IV), or a pharmaceuticallyacceptable salt or solvate thereof, wherein Y is ═C(R₁₅)— and Z is ═N—.In some embodiments is a compound of Formula (IV), or a pharmaceuticallyacceptable salt or solvate thereof, wherein Y is ═C(R₁₅)—, Z is ═N—, andR₁₅ is hydrogen. In some embodiments is a compound of Formula (IV), or apharmaceutically acceptable salt or solvate thereof, wherein Y is═C(R₁₅)—, Z is ═N—, and R₁₅ is halogen. In some embodiments is acompound of Formula (IV), or a pharmaceutically acceptable salt orsolvate thereof, wherein Y is ═C(R₁₅)—, Z is ═N—, and R₁₅ is C₁-C₆alkyl.In some embodiments is a compound of Formula (IV), or a pharmaceuticallyacceptable salt or solvate thereof, wherein Y is ═C(R₁₅)—, Z is ═N—, andR₁₅ is C₁-C₆haloalkyl.

In some embodiments is a compound of Formula (IV), or a pharmaceuticallyacceptable salt or solvate thereof, wherein Y is ═N— and Z is ═N—.

In some embodiments is a compound of Formula (IV), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₇ and R₈ are independentlyselected from hydrogen, halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, andC₁-C₆alkoxy. In some embodiments is a compound of Formula (IV), or apharmaceutically acceptable salt or solvate thereof, wherein R₇ and R₈are each hydrogen. In some embodiments is a compound of Formula (IV), ora pharmaceutically acceptable salt or solvate thereof, wherein R₇ and R₈are each halogen. In some embodiments is a compound of Formula (IV), ora pharmaceutically acceptable salt or solvate thereof, wherein R₇ and R₈are each C₁-C₆alkyl. In some embodiments is a compound of Formula (IV),or a pharmaceutically acceptable salt or solvate thereof, wherein R₇ ishydrogen and R₈ is halogen. In some embodiments is a compound of Formula(IV), or a pharmaceutically acceptable salt or solvate thereof, whereinR₇ is hydrogen and R₈ is C₁-C₆alkyl. In some embodiments is a compoundof Formula (IV), or a pharmaceutically acceptable salt or solvatethereof, wherein R₇ is hydrogen and R₈ is C₁-C₆haloalkyl. In someembodiments is a compound of Formula (IV), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₇ is hydrogen and R₈ isC₁-C₆alkoxy. In some embodiments is a compound of Formula (IV), or apharmaceutically acceptable salt or solvate thereof, wherein R₇ ishydrogen and R₈ is —CN. In some embodiments is a compound of Formula(IV), or a pharmaceutically acceptable salt or solvate thereof, whereinR₇ is halogen and R₈ is hydrogen. In some embodiments is a compound ofFormula (IV), or a pharmaceutically acceptable salt or solvate thereof,wherein R₇ is C₁-C₆alkyl and R₈ is hydrogen. In some embodiments is acompound of Formula (IV), or a pharmaceutically acceptable salt orsolvate thereof, wherein R₇ is C₁-C₆haloalkyl and R₈ is hydrogen. Insome embodiments is a compound of Formula (IV), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₇ is C₁-C₆alkoxy and R₈ ishydrogen. In some embodiments is a compound of Formula (IV), or apharmaceutically acceptable salt or solvate thereof, wherein R₇ is —CNand R₈ is hydrogen.

In some embodiments is a compound of Formula (IV), or a pharmaceuticallyacceptable salt or solvate thereof, wherein X is —O—. In someembodiments is a compound of Formula (IV), or a pharmaceuticallyacceptable salt or solvate thereof, wherein X is —O— and n is 2. In someembodiments is a compound of Formula (IV), or a pharmaceuticallyacceptable salt or solvate thereof, wherein X is —O—, n is 2, and eachR₁ and each R₂ are hydrogen. In some embodiments is a compound ofFormula (IV), or a pharmaceutically acceptable salt or solvate thereof,wherein X is —O—, n is 2, each R₁ is hydrogen, and one R₂ is hydrogenand one R₂ is C₁-C₆alkyl. In some embodiments is a compound of Formula(IV), or a pharmaceutically acceptable salt or solvate thereof, whereinX is —O— and n is 3. In some embodiments is a compound of Formula (IV),or a pharmaceutically acceptable salt or solvate thereof, wherein X is—O—, n is 3, and each R₁ and each R₂ are hydrogen. In some embodimentsis a compound of Formula (IV), or a pharmaceutically acceptable salt orsolvate thereof, wherein X is —O—, n is 3, one R₁ is C₁-C₆alkyl and oneR₂ is C₁-C₆alkyl and the remaining R₁ and R₂ are each hydrogen.

In some embodiments is a compound of Formula (IV), or a pharmaceuticallyacceptable salt or solvate thereof, wherein X is —C(R₉)(R₁₀)—. In someembodiments is a compound of Formula (IV), or a pharmaceuticallyacceptable salt or solvate thereof, wherein X is —CH₂—. In someembodiments is a compound of Formula (IV), or a pharmaceuticallyacceptable salt or solvate thereof, wherein X is —CH₂— and n is 1. Insome embodiments is a compound of Formula (IV), or a pharmaceuticallyacceptable salt or solvate thereof, wherein X is —CH₂—, n is 1, and R₁and R₂ are hydrogen. In some embodiments is a compound of Formula (IV),or a pharmaceutically acceptable salt or solvate thereof, wherein X is—CH₂— and n is 2. In some embodiments is a compound of Formula (IV), ora pharmaceutically acceptable salt or solvate thereof, wherein X is—CH₂—, n is 2, and each R₁ and each R₂ are hydrogen. In some embodimentsis a compound of Formula (IV), or a pharmaceutically acceptable salt orsolvate thereof, wherein X is —CH₂— and n is 3. In some embodiments is acompound of Formula (IV), or a pharmaceutically acceptable salt orsolvate thereof, wherein X is —CH₂—, n is 3, and each R₁ and each R₂ arehydrogen.

In some embodiments is a compound of Formula (IV), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₄ is selected from hydrogenand C₁-C₆alkyl. In some embodiments is a compound of Formula (IV), or apharmaceutically acceptable salt or solvate thereof, wherein R₄ ishydrogen. In some embodiments is a compound of Formula (IV), or apharmaceutically acceptable salt or solvate thereof, wherein R₄ isC₁-C₆alkyl.

In some embodiments is a compound of Formula (IV), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₅ is selected from hydrogenand C₁-C₆alkyl. In some embodiments is a compound of Formula (IV), or apharmaceutically acceptable salt or solvate thereof, wherein R₅ ishydrogen. In some embodiments is a compound of Formula (IV), or apharmaceutically acceptable salt or solvate thereof, wherein R₅ isC₁-C₆alkyl.

In some embodiments is a compound of Formula (IV), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₁₃ is hydrogen. In someembodiments is a compound of Formula (IV), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₅ and R₁₃ together with theatoms to which they are attached are combined to form a 5- or 6-memberedheterocycloalkyl ring or a 5- or 6-membered heteroaryl ring, wherein the5- or 6-membered heterocycloalkyl ring or 5- or 6-membered heteroarylring is optionally substituted with 1, 2, or 3 groups selected fromhalogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, and C₁-C₆haloalkoxy.In some embodiments is a compound of Formula (IV), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₅ and R₁₃ together with theatoms to which they are attached are combined to form a 5- or 6-memberedheterocycloalkyl ring, wherein the 5- or 6-membered heterocycloalkylring is optionally substituted with 1, 2, or 3 groups selected fromhalogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, and C₁-C₆haloalkoxy.In some embodiments is a compound of Formula (IV), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₅ and R₁₃ together with theatoms to which they are attached are combined to form a 5- or 6-memberedheteroaryl ring, wherein the 5- or 6-membered heteroaryl ring isoptionally substituted with 1, 2, or 3 groups selected from halogen,C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, and C₁-C₆haloalkoxy.

In some embodiments is a compound of Formula (IV), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₄ is hydrogen and R₅ isC₁-C₆alkyl. In some embodiments is a compound of Formula (IV), or apharmaceutically acceptable salt or solvate thereof, wherein R₄ and R₅are hydrogen. In some embodiments is a compound of Formula (IV), or apharmaceutically acceptable salt or solvate thereof, wherein R₄ and R₅are C₁-C₆alkyl.

In some embodiments is a compound of Formula (IV), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₃ is hydrogen. In someembodiments is a compound of Formula (IV), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₃ is C₁-C₆alkyl.

In some embodiments is a compound of Formula (IV), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₆ is hydrogen. In someembodiments is a compound of Formula (IV), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₆ is C₁-C₆alkyl.

In some embodiments is a compound of Formula (IV), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₁₈ is hydrogen. In someembodiments is a compound of Formula (IV), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₁₈ is deuterium. In someembodiments is a compound of Formula (IV), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₁₈ is halogen. In someembodiments is a compound of Formula (IV), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₁₈ is C₁-C₆alkyl. In someembodiments is a compound of Formula (IV), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₁₈ is C₁-C₆deuteroalkyl.

In some embodiments, provided herein is a compound of Formula (IVa), ora pharmaceutically acceptable salt or solvate thereof:

wherein:

-   -   X is —O— or —C(R₉)(R₁₀)—;    -   each R₁ is independently selected from hydrogen and C₁-C₆alkyl;    -   each R₂ is independently selected from hydrogen and C₁-C₆alkyl;    -   R₃ is hydrogen or C₁-C₆alkyl;    -   R₄ and R₅ are independently selected from hydrogen, C₁-C₆alkyl,        C₁-C₆heteroalkyl, C₃-C₆cycloalkyl, and C₂-C₉heterocycloalkyl;    -   R₆ is hydrogen or C₁-C₆alkyl;    -   R₇ and R₈ are independently selected from hydrogen, halogen,        C₁-C₆alkyl, —C₁-C₆alkyl-OH, C₁-C₆haloalkyl, C₁-C₆alkoxy,        C₃-C₆cycloalkyl, C₂-C₉heterocycloalkyl, C₂-C₉heteroaryl,        C₆-C₁₀aryl, —OR₁₁, —N(R₁₁)₂, —CN, —C(═O)R₁₂, —C(═O)OR₁₁,        —C(═O)N(R₁₁)₂, —NR₁₁C(═O)R₁₂, —NR₁₁S(═O)₂R₁₂, —S(═O)₂R₁₂, and        —S(═O)₂N(R₁₁)₂, wherein C₃-C₆cycloalkyl, C₂-C₉heterocycloalkyl,        C₂-C₉heteroaryl, or C₆-C₁₀aryl are optionally substituted with        1, 2, or 3 groups selected from halogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆alkoxy, and C₁-C₆haloalkoxy;    -   R₉ and R₁₀ are independently selected from hydrogen and        C₁-C₆alkyl;    -   each R₁ is independently selected from hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆heteroalkyl, and phenyl, wherein phenyl is        optionally substituted with 1, 2, or 3 groups selected from        halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy,        C₁-C₆haloalkoxy, C₂-C₉heterocycloalkyl, C₂-C₉heteroaryl, —OR₁₄,        —N(R₁₄)₂, —C(═O)OR₁₄, and —C(═O)N(R₁₄)₂;    -   each R₁₂ is independently selected from C₁-C₆alkyl and        C₁-C₆heteroalkyl;    -   each R₁₄ is independently selected from hydrogen, C₁-C₆alkyl,        and C₁-C₆haloalkyl;    -   R₁₅ and R₁₆ are independently selected from hydrogen, halogen,        C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆heteroalkyl,        —OR₁₁, —N(R₁₁)₂, —CN, —C(═O)R₁₂, —C(═O)OR₁₁, —C(═O)N(R₁₁)₂,        —NR₁₁C(═O)R₁₂, —NR₁₁S(═O)₂R₁₂, —S(═O)₂R₁₂, and —S(═O)₂N(R₁₁)₂;        and    -   n is 1, 2, 3, or 4.

In some embodiments is a compound of Formula (IVa), or apharmaceutically acceptable salt or solvate thereof, wherein R₁₅ ishydrogen and R₁₆ is hydrogen. In some embodiments is a compound ofFormula (IVa), or a pharmaceutically acceptable salt or solvate thereof,wherein R₁₅ is hydrogen and R₁₆ is halogen. In some embodiments is acompound of Formula (IVa), or a pharmaceutically acceptable salt orsolvate thereof, wherein R₁₅ is halogen and R₁₆ is halogen. In someembodiments is a compound of Formula (IVa), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₁₅ is hydrogen and R₁₆ isC₁-C₆alkyl. In some embodiments is a compound of Formula (IVa), or apharmaceutically acceptable salt or solvate thereof, wherein R₁₅ ishydrogen and R₁₆ is C₁-C₆haloalkyl. In some embodiments is a compound ofFormula (IVa), or a pharmaceutically acceptable salt or solvate thereof,wherein R₁₅ is halogen and R₁₆ is hydrogen.

In some embodiments is a compound of Formula (IVa), or apharmaceutically acceptable salt or solvate thereof, wherein R₇ and R₈are independently selected from hydrogen, halogen, C₁-C₆alkyl,C₁-C₆haloalkyl, and C₁-C₆alkoxy. In some embodiments is a compound ofFormula (IVa), or a pharmaceutically acceptable salt or solvate thereof,wherein R₇ and R₈ are each hydrogen. In some embodiments is a compoundof Formula (IVa), or a pharmaceutically acceptable salt or solvatethereof, wherein R₇ and R₈ are each halogen. In some embodiments is acompound of Formula (IVa), or a pharmaceutically acceptable salt orsolvate thereof, wherein R₇ and R₈ are each C₁-C₆alkyl. In someembodiments is a compound of Formula (IVa), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₇ is hydrogen and R₈ ishalogen. In some embodiments is a compound of Formula (IVa), or apharmaceutically acceptable salt or solvate thereof, wherein R₇ ishydrogen and R₈ is C₁-C₆alkyl. In some embodiments is a compound ofFormula (IVa), or a pharmaceutically acceptable salt or solvate thereof,wherein R₇ is hydrogen and R₈ is C₁-C₆haloalkyl. In some embodiments isa compound of Formula (IVa), or a pharmaceutically acceptable salt orsolvate thereof, wherein R₇ is hydrogen and R₈ is C₁-C₆alkoxy. In someembodiments is a compound of Formula (IVa), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₇ is hydrogen and R₈ is—CN. In some embodiments is a compound of Formula (IVa), or apharmaceutically acceptable salt or solvate thereof, wherein R₇ ishalogen and R₈ is hydrogen. In some embodiments is a compound of Formula(IVa), or a pharmaceutically acceptable salt or solvate thereof, whereinR₇ is C₁-C₆alkyl and R₈ is hydrogen. In some embodiments is a compoundof Formula (IVa), or a pharmaceutically acceptable salt or solvatethereof, wherein R₇ is C₁-C₆haloalkyl and R₈ is hydrogen. In someembodiments is a compound of Formula (IVa), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₇ is C₁-C₆alkoxy and R₈ ishydrogen. In some embodiments is a compound of Formula (IVa), or apharmaceutically acceptable salt or solvate thereof, wherein R₇ is —CNand R₈ is hydrogen.

In some embodiments is a compound of Formula (IVa), or apharmaceutically acceptable salt or solvate thereof, wherein X is —O—.In some embodiments is a compound of Formula (IVa), or apharmaceutically acceptable salt or solvate thereof, wherein X is —O—and n is 2. In some embodiments is a compound of Formula (IVa), or apharmaceutically acceptable salt or solvate thereof, wherein X is —O—, nis 2, and each R₁ and each R₂ are hydrogen. In some embodiments is acompound of Formula (IVa), or a pharmaceutically acceptable salt orsolvate thereof, wherein X is —O—, n is 2, each R₁ is hydrogen, and oneR₂ is hydrogen and one R₂ is C₁-C₆alkyl. In some embodiments is acompound of Formula (IVa), or a pharmaceutically acceptable salt orsolvate thereof, wherein X is —O— and n is 3. In some embodiments is acompound of Formula (IVa), or a pharmaceutically acceptable salt orsolvate thereof, wherein X is —O—, n is 3, and each R₁ and each R₂ arehydrogen. In some embodiments is a compound of Formula (IVa), or apharmaceutically acceptable salt or solvate thereof, wherein X is —O—, nis 3, one R₁ is C₁-C₆alkyl and one R₂ is C₁-C₆alkyl and the remaining R₁and R₂ are each hydrogen.

In some embodiments is a compound of Formula (IVa), or apharmaceutically acceptable salt or solvate thereof, wherein X is—C(R₉)(R₁₀)—. In some embodiments is a compound of Formula (IVa), or apharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—.In some embodiments is a compound of Formula (IVa), or apharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—and n is 1. In some embodiments is a compound of Formula (IVa), or apharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—,n is 1, and R₁ and R₂ are hydrogen. In some embodiments is a compound ofFormula (IVa), or a pharmaceutically acceptable salt or solvate thereof,wherein X is —CH₂— and n is 2. In some embodiments is a compound ofFormula (IVa), or a pharmaceutically acceptable salt or solvate thereof,wherein X is —CH₂—, n is 2, and each R₁ and each R₂ are hydrogen. Insome embodiments is a compound of Formula (IVa), or a pharmaceuticallyacceptable salt or solvate thereof, wherein X is —CH₂— and n is 3. Insome embodiments is a compound of Formula (IVa), or a pharmaceuticallyacceptable salt or solvate thereof, wherein X is —CH₂—, n is 3, and eachR₁ and each R₂ are hydrogen.

In some embodiments is a compound of Formula (IVa), or apharmaceutically acceptable salt or solvate thereof, wherein R₄ and R₅are independently selected from hydrogen and C₁-C₆alkyl. In someembodiments is a compound of Formula (IVa), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₄ is hydrogen and R₅ isC₁-C₆alkyl. In some embodiments is a compound of Formula (IVa), or apharmaceutically acceptable salt or solvate thereof, wherein R₄ and R₅are hydrogen. In some embodiments is a compound of Formula (IVa), or apharmaceutically acceptable salt or solvate thereof, wherein R₄ and R₅are C₁-C₆alkyl.

In some embodiments is a compound of Formula (IVa), or apharmaceutically acceptable salt or solvate thereof, wherein R₃ ishydrogen. In some embodiments is a compound of Formula (IVa), or apharmaceutically acceptable salt or solvate thereof, wherein R₃ isC₁-C₆alkyl.

In some embodiments is a compound of Formula (IVa), or apharmaceutically acceptable salt or solvate thereof, wherein R₆ ishydrogen. In some embodiments is a compound of Formula (IVa), or apharmaceutically acceptable salt or solvate thereof, wherein R₆ isC₁-C₆alkyl.

In some embodiments, provided herein is a compound of Formula (IVb), ora pharmaceutically acceptable salt or solvate thereof:

wherein:

-   -   X is —O— or —C(R₉)(R₁₀)—;    -   each R₁ is independently selected from hydrogen and C₁-C₆alkyl;    -   each R₂ is independently selected from hydrogen and C₁-C₆alkyl;    -   R₃ is hydrogen or C₁-C₆alkyl;    -   R₄ and R₅ are independently selected from hydrogen, C₁-C₆alkyl,        C₁-C₆heteroalkyl, C₃-C₆cycloalkyl, and C₂-C₉heterocycloalkyl;    -   R₆ is hydrogen or C₁-C₆alkyl;    -   R₇ and R₈ are independently selected from hydrogen, halogen,        C₁-C₆alkyl, —C₁-C₆alkyl-OH, C₁-C₆haloalkyl, C₁-C₆alkoxy,        C₃-C₆cycloalkyl, C₂-C₉heterocycloalkyl, C₂-C₉heteroaryl,        C₆-C₁₀aryl, —OR₁₁, —N(R₁₁)₂, —CN, —C(═O)R₁₂, —C(═O)OR₁₁,        —C(═O)N(R₁₁)₂, —NR₁₁C(═O)R₁₂, —NR₁₁S(═O)₂R₁₂, —S(═O)₂R₁₂, and        —S(═O)₂N(R₁₁)₂, wherein C₃-C₆cycloalkyl, C₂-C₉heterocycloalkyl,        C₂-C₉heteroaryl, or C₆-C₁₀aryl are optionally substituted with        1, 2, or 3 groups selected from halogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆alkoxy, and C₁-C₆haloalkoxy;    -   R₉ and R₁₀ are independently selected from hydrogen and        C₁-C₆alkyl;    -   each R₁ is independently selected from hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆heteroalkyl, and phenyl, wherein phenyl is        optionally substituted with 1, 2, or 3 groups selected from        halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy,        C₁-C₆haloalkoxy, C₂-C₉heterocycloalkyl, C₂-C₉heteroaryl, —OR₁₄,        —N(R₁₄)₂, —C(═O)OR₁₄, and —C(═O)N(R₁₄)₂;    -   each R₁₂ is independently selected from C₁-C₆alkyl and        C₁-C₆heteroalkyl;    -   each R₁₄ is independently selected from hydrogen, C₁-C₆alkyl,        and C₁-C₆haloalkyl;    -   R₁₆ is selected from hydrogen, halogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆heteroalkyl, —OR₁₁, —N(R₁₁)₂,        —CN, —C(═O)R₁₂, —C(═O)OR₁₁, —C(═O)N(R₁₁)₂, —NR₁₁C(═O)R₁₂,        —NR₁₁S(═O)₂R₁₂, —S(═O)₂R₁₂, and —S(═O)₂N(R₁₁)₂; and    -   n is 1, 2, 3, or 4.

In some embodiments is a compound of Formula (IVb), or apharmaceutically acceptable salt or solvate thereof, wherein R₁₆ ishydrogen. In some embodiments is a compound of Formula (IVb), or apharmaceutically acceptable salt or solvate thereof, wherein R₁₆ ishalogen. In some embodiments is a compound of Formula (IVb), or apharmaceutically acceptable salt or solvate thereof, wherein R₁₆ isC₁-C₆alkyl. In some embodiments is a compound of Formula (IVb), or apharmaceutically acceptable salt or solvate thereof, wherein R₁₆ isC₁-C₆haloalkyl.

In some embodiments is a compound of Formula (IVb), or apharmaceutically acceptable salt or solvate thereof, wherein R₇ and R₈are independently selected from hydrogen, halogen, C₁-C₆alkyl,C₁-C₆haloalkyl, and C₁-C₆alkoxy. In some embodiments is a compound ofFormula (IVb), or a pharmaceutically acceptable salt or solvate thereof,wherein R₇ and R₈ are each hydrogen. In some embodiments is a compoundof Formula (IVb), or a pharmaceutically acceptable salt or solvatethereof, wherein R₇ and R₈ are each halogen. In some embodiments is acompound of Formula (IVb), or a pharmaceutically acceptable salt orsolvate thereof, wherein R₇ and R₈ are each C₁-C₆alkyl. In someembodiments is a compound of Formula (IVb), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₇ is hydrogen and R₈ ishalogen. In some embodiments is a compound of Formula (IVb), or apharmaceutically acceptable salt or solvate thereof, wherein R₇ ishydrogen and R₈ is C₁-C₆alkyl. In some embodiments is a compound ofFormula (IVb), or a pharmaceutically acceptable salt or solvate thereof,wherein R₇ is hydrogen and R₈ is C₁-C₆haloalkyl. In some embodiments isa compound of Formula (IVb), or a pharmaceutically acceptable salt orsolvate thereof, wherein R₇ is hydrogen and R₈ is C₁-C₆alkoxy. In someembodiments is a compound of Formula (IVb), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₇ is hydrogen and R₈ is—CN. In some embodiments is a compound of Formula (IVb), or apharmaceutically acceptable salt or solvate thereof, wherein R₇ ishalogen and R₈ is hydrogen. In some embodiments is a compound of Formula(IVb), or a pharmaceutically acceptable salt or solvate thereof, whereinR₇ is C₁-C₆alkyl and R₈ is hydrogen. In some embodiments is a compoundof Formula (IVb), or a pharmaceutically acceptable salt or solvatethereof, wherein R₇ is C₁-C₆haloalkyl and R₈ is hydrogen. In someembodiments is a compound of Formula (IVb), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₇ is C₁-C₆alkoxy and R₈ ishydrogen. In some embodiments is a compound of Formula (IVb), or apharmaceutically acceptable salt or solvate thereof, wherein R₇ is —CNand R₈ is hydrogen.

In some embodiments is a compound of Formula (IVb), or apharmaceutically acceptable salt or solvate thereof, wherein X is —O—.In some embodiments is a compound of Formula (IVb), or apharmaceutically acceptable salt or solvate thereof, wherein X is —O—and n is 2. In some embodiments is a compound of Formula (IVb), or apharmaceutically acceptable salt or solvate thereof, wherein X is —O—, nis 2, and each R₁ and each R₂ are hydrogen. In some embodiments is acompound of Formula (IVb), or a pharmaceutically acceptable salt orsolvate thereof, wherein X is —O—, n is 2, each R₁ is hydrogen, and oneR₂ is hydrogen and one R₂ is C₁-C₆alkyl. In some embodiments is acompound of Formula (IVb), or a pharmaceutically acceptable salt orsolvate thereof, wherein X is —O— and n is 3. In some embodiments is acompound of Formula (IVb), or a pharmaceutically acceptable salt orsolvate thereof, wherein X is —O—, n is 3, and each R₁ and each R₂ arehydrogen. In some embodiments is a compound of Formula (IVb), or apharmaceutically acceptable salt or solvate thereof, wherein X is —O—, nis 3, one R₁ is C₁-C₆alkyl and one R₂ is C₁-C₆alkyl and the remaining R₁and R₂ are each hydrogen.

In some embodiments is a compound of Formula (IVb), or apharmaceutically acceptable salt or solvate thereof, wherein X is—C(R₉)(R₁₀)—. In some embodiments is a compound of Formula (IVb), or apharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—.In some embodiments is a compound of Formula (IVb), or apharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—and n is 1. In some embodiments is a compound of Formula (IVb), or apharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—,n is 1, and R₁ and R₂ are hydrogen. In some embodiments is a compound ofFormula (IVb), or a pharmaceutically acceptable salt or solvate thereof,wherein X is —CH₂— and n is 2. In some embodiments is a compound ofFormula (IVb), or a pharmaceutically acceptable salt or solvate thereof,wherein X is —CH₂—, n is 2, and each R₁ and each R₂ are hydrogen. Insome embodiments is a compound of Formula (IVb), or a pharmaceuticallyacceptable salt or solvate thereof, wherein X is —CH₂— and n is 3. Insome embodiments is a compound of Formula (IVb), or a pharmaceuticallyacceptable salt or solvate thereof, wherein X is —CH₂—, n is 3, and eachR₁ and each R₂ are hydrogen.

In some embodiments is a compound of Formula (IVb), or apharmaceutically acceptable salt or solvate thereof, wherein R₄ and R₅are independently selected from hydrogen and C₁-C₆alkyl. In someembodiments is a compound of Formula (IVb), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₄ is hydrogen and R₅ isC₁-C₆alkyl. In some embodiments is a compound of Formula (IVb), or apharmaceutically acceptable salt or solvate thereof, wherein R₄ and R₅are hydrogen. In some embodiments is a compound of Formula (IVb), or apharmaceutically acceptable salt or solvate thereof, wherein R₄ and R₅are C₁-C₆alkyl.

In some embodiments is a compound of Formula (IVb), or apharmaceutically acceptable salt or solvate thereof, wherein R₃ ishydrogen. In some embodiments is a compound of Formula (IVb), or apharmaceutically acceptable salt or solvate thereof, wherein R₃ isC₁-C₆alkyl.

In some embodiments is a compound of Formula (IVb), or apharmaceutically acceptable salt or solvate thereof, wherein R₆ ishydrogen. In some embodiments is a compound of Formula (IVb), or apharmaceutically acceptable salt or solvate thereof, wherein R₆ isC₁-C₆alkyl.

In some embodiments, provided herein is a compound of Formula (IVc), ora pharmaceutically acceptable salt or solvate thereof:

wherein:

-   -   X is —O— or —C(R₉)(R₁₀)—;    -   each R₁ is independently selected from hydrogen and C₁-C₆alkyl;    -   each R₂ is independently selected from hydrogen and C₁-C₆alkyl;    -   R₃ is hydrogen or C₁-C₆alkyl;    -   R₄ and R₅ are independently selected from hydrogen, C₁-C₆alkyl,        C₁-C₆heteroalkyl, C₃-C₆cycloalkyl, and C₂-C₉heterocycloalkyl;    -   R₆ is hydrogen or C₁-C₆alkyl;    -   R₇ and R₈ are independently selected from hydrogen, halogen,        C₁-C₆alkyl, —C₁-C₆alkyl-OH, C₁-C₆haloalkyl, C₁-C₆alkoxy,        C₃-C₆cycloalkyl, C₂-C₉heterocycloalkyl, C₂-C₉heteroaryl,        C₆-C₁₀aryl, —OR₁, —N(R₁₁)₂, —CN, —C(═O)R₁₂, —C(═O)OR₁,        —C(═O)N(R₁₁)₂, —NR₁₁C(═O)R₁₂, —NR₁₁S(═O)₂R₁₂, —S(═O)₂R₁₂, and        —S(═O)₂N(R₁₁)₂, wherein C₃-C₆cycloalkyl, C₂-C₉heterocycloalkyl,        C₂-C₉heteroaryl, or C₆-C₁₀aryl are optionally substituted with        1, 2, or 3 groups selected from halogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆alkoxy, and C₁-C₆haloalkoxy;    -   R₉ and R₁₀ are independently selected from hydrogen and        C₁-C₆alkyl;    -   each Rn is independently selected from hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆heteroalkyl, and phenyl, wherein phenyl is        optionally substituted with 1, 2, or 3 groups selected from        halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy,        C₁-C₆haloalkoxy, C₂-C₉heterocycloalkyl, C₂-C₉heteroaryl, —OR₁₄,        —N(R₁₄)₂, —C(═O)OR₁₄, and —C(═O)N(R₁₄)₂;    -   each R₁₂ is independently selected from C₁-C₆alkyl and        C₁-C₆heteroalkyl;    -   each R₁₄ is independently selected from hydrogen, C₁-C₆alkyl,        and C₁-C₆haloalkyl;    -   R₁₅ is selected from hydrogen, halogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆heteroalkyl, —OR₁₁, —N(R₁₁)₂,        —CN, —C(═O)R₁₂, —C(═O)OR₁₁, —C(═O)N(R₁₁)₂, —NR₁₁C(═O)R₁₂,        —NR₁₁S(═O)₂R₁₂, —S(═O)₂R₁₂, and —S(═O)₂N(R₁₁)₂; and    -   n is 1, 2, 3, or 4.

In some embodiments is a compound of Formula (IVc), or apharmaceutically acceptable salt or solvate thereof, wherein R₁₅ ishydrogen. In some embodiments is a compound of Formula (IVc), or apharmaceutically acceptable salt or solvate thereof, wherein R₁₅ ishalogen. In some embodiments is a compound of Formula (IVc), or apharmaceutically acceptable salt or solvate thereof, wherein R₁₅ isC₁-C₆alkyl. In some embodiments is a compound of Formula (IVc), or apharmaceutically acceptable salt or solvate thereof, wherein R₁₅ isC₁-C₆haloalkyl.

In some embodiments is a compound of Formula (IVc), or apharmaceutically acceptable salt or solvate thereof, wherein R₇ and R₈are independently selected from hydrogen, halogen, C₁-C₆alkyl,C₁-C₆haloalkyl, and C₁-C₆alkoxy. In some embodiments is a compound ofFormula (IVc), or a pharmaceutically acceptable salt or solvate thereof,wherein R₇ and R₈ are each hydrogen. In some embodiments is a compoundof Formula (IVc), or a pharmaceutically acceptable salt or solvatethereof, wherein R₇ and R₈ are each halogen. In some embodiments is acompound of Formula (IVc), or a pharmaceutically acceptable salt orsolvate thereof, wherein R₇ and R₈ are each C₁-C₆alkyl. In someembodiments is a compound of Formula (IVc), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₇ is hydrogen and R₈ ishalogen. In some embodiments is a compound of Formula (IVc), or apharmaceutically acceptable salt or solvate thereof, wherein R₇ ishydrogen and R₈ is C₁-C₆alkyl. In some embodiments is a compound ofFormula (IVc), or a pharmaceutically acceptable salt or solvate thereof,wherein R₇ is hydrogen and R₈ is C₁-C₆haloalkyl. In some embodiments isa compound of Formula (IVc), or a pharmaceutically acceptable salt orsolvate thereof, wherein R₇ is hydrogen and R₈ is C₁-C₆alkoxy. In someembodiments is a compound of Formula (IVc), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₇ is hydrogen and R₈ is—CN. In some embodiments is a compound of Formula (IVc), or apharmaceutically acceptable salt or solvate thereof, wherein R₇ ishalogen and R₈ is hydrogen. In some embodiments is a compound of Formula(IVc), or a pharmaceutically acceptable salt or solvate thereof, whereinR₇ is C₁-C₆alkyl and R₈ is hydrogen. In some embodiments is a compoundof Formula (IVc), or a pharmaceutically acceptable salt or solvatethereof, wherein R₇ is C₁-C₆haloalkyl and R₈ is hydrogen. In someembodiments is a compound of Formula (IVc), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₇ is C₁-C₆alkoxy and R₈ ishydrogen. In some embodiments is a compound of Formula (IVc), or apharmaceutically acceptable salt or solvate thereof, wherein R₇ is —CNand R₈ is hydrogen.

In some embodiments is a compound of Formula (IVc), or apharmaceutically acceptable salt or solvate thereof, wherein X is —O—.In some embodiments is a compound of Formula (IVc), or apharmaceutically acceptable salt or solvate thereof, wherein X is —O—and n is 2. In some embodiments is a compound of Formula (IVc), or apharmaceutically acceptable salt or solvate thereof, wherein X is —O—, nis 2, and each R₁ and each R₂ are hydrogen. In some embodiments is acompound of Formula (IVc), or a pharmaceutically acceptable salt orsolvate thereof, wherein X is —O—, n is 2, each R₁ is hydrogen, and oneR₂ is hydrogen and one R₂ is C₁-C₆alkyl. In some embodiments is acompound of Formula (IVc), or a pharmaceutically acceptable salt orsolvate thereof, wherein X is —O— and n is 3. In some embodiments is acompound of Formula (IVc), or a pharmaceutically acceptable salt orsolvate thereof, wherein X is —O—, n is 3, and each R₁ and each R₂ arehydrogen. In some embodiments is a compound of Formula (IVc), or apharmaceutically acceptable salt or solvate thereof, wherein X is —O—, nis 3, one R₁ is C₁-C₆alkyl and one R₂ is C₁-C₆alkyl and the remaining R₁and R₂ are each hydrogen.

In some embodiments is a compound of Formula (IVc), or apharmaceutically acceptable salt or solvate thereof, wherein X is—C(R₉)(R₁₀)—. In some embodiments is a compound of Formula (IVc), or apharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—.In some embodiments is a compound of Formula (IVc), or apharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—and n is 1. In some embodiments is a compound of Formula (IVc), or apharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—,n is 1, and R₁ and R₂ are hydrogen. In some embodiments is a compound ofFormula (IVc), or a pharmaceutically acceptable salt or solvate thereof,wherein X is —CH₂— and n is 2. In some embodiments is a compound ofFormula (IVc), or a pharmaceutically acceptable salt or solvate thereof,wherein X is —CH₂—, n is 2, and each R₁ and each R₂ are hydrogen. Insome embodiments is a compound of Formula (IVc), or a pharmaceuticallyacceptable salt or solvate thereof, wherein X is —CH₂— and n is 3. Insome embodiments is a compound of Formula (IVc), or a pharmaceuticallyacceptable salt or solvate thereof, wherein X is —CH₂—, n is 3, and eachR₁ and each R₂ are hydrogen.

In some embodiments is a compound of Formula (IVc), or apharmaceutically acceptable salt or solvate thereof, wherein R₄ and R₅are independently selected from hydrogen and C₁-C₆alkyl. In someembodiments is a compound of Formula (IVc), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₄ is hydrogen and R₅ isC₁-C₆alkyl. In some embodiments is a compound of Formula (IVc), or apharmaceutically acceptable salt or solvate thereof, wherein R₄ and R₅are hydrogen. In some embodiments is a compound of Formula (IVc), or apharmaceutically acceptable salt or solvate thereof, wherein R₄ and R₅are C₁-C₆alkyl.

In some embodiments is a compound of Formula (IVc), or apharmaceutically acceptable salt or solvate thereof, wherein R₃ ishydrogen. In some embodiments is a compound of Formula (IVc), or apharmaceutically acceptable salt or solvate thereof, wherein R₃ isC₁-C₆alkyl.

In some embodiments is a compound of Formula (IVc), or apharmaceutically acceptable salt or solvate thereof, wherein R₆ ishydrogen. In some embodiments is a compound of Formula (IVc), or apharmaceutically acceptable salt or solvate thereof, wherein R₆ isC₁-C₆alkyl.

In some embodiments, provided herein is a compound of Formula (IVd), ora pharmaceutically acceptable salt or solvate thereof:

wherein:

-   -   X is —O— or —C(R₉)(R₁₀)—;    -   each R₁ is independently selected from hydrogen and C₁-C₆alkyl;    -   each R₂ is independently selected from hydrogen and C₁-C₆alkyl;    -   R₃ is hydrogen or C₁-C₆alkyl;    -   R₄ and R₅ are independently selected from hydrogen, C₁-C₆alkyl,        C₁-C₆heteroalkyl, C₃-C₆cycloalkyl, and C₂-C₉heterocycloalkyl;    -   R₆ is hydrogen or C₁-C₆alkyl;    -   R₇ and R₈ are independently selected from hydrogen, halogen,        C₁-C₆alkyl, —C₁-C₆alkyl-OH, C₁-C₆haloalkyl, C₁-C₆alkoxy,        C₃-C₆cycloalkyl, C₂-C₉heterocycloalkyl, C₂-C₉heteroaryl,        C₆-C₁₀aryl, —OR₁₁, —N(R₁₁)₂, —CN, —C(═O)R₁₂, —C(═O)OR₁₁,        —C(═O)N(R₁₁)₂, —NR₁₁C(═O)R₁₂, —NR₁₁S(═O)₂R₁₂, —S(═O)₂R₁₂, and        —S(═O)₂N(R₁₁)₂, wherein C₃-C₆cycloalkyl, C₂-C₉heterocycloalkyl,        C₂-C₉heteroaryl, or C₆-C₁₀aryl are optionally substituted with        1, 2, or 3 groups selected from halogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆alkoxy, and C₁-C₆haloalkoxy;    -   R₉ and R₁₀ are independently selected from hydrogen and        C₁-C₆alkyl;    -   each R₁ is independently selected from hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆heteroalkyl, and phenyl, wherein phenyl is        optionally substituted with 1, 2, or 3 groups selected from        halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy,        C₁-C₆haloalkoxy, C₂-C₉heterocycloalkyl, C₂-C₉heteroaryl, —OR₁₄,        —N(R₁₄)₂, —C(═O)OR₁₄, and —C(═O)N(R₁₄)₂;    -   each R₁₂ is independently selected from C₁-C₆alkyl and        C₁-C₆heteroalkyl;    -   each R₁₄ is independently selected from hydrogen, C₁-C₆alkyl,        and C₁-C₆haloalkyl; and    -   n is 1, 2, 3, or 4.

In some embodiments is a compound of Formula (IVd), or apharmaceutically acceptable salt or solvate thereof, wherein R₇ and R₈are independently selected from hydrogen, halogen, C₁-C₆alkyl,C₁-C₆haloalkyl, and C₁-C₆alkoxy. In some embodiments is a compound ofFormula (IVd), or a pharmaceutically acceptable salt or solvate thereof,wherein R₇ and R₈ are each hydrogen. In some embodiments is a compoundof Formula (IVd), or a pharmaceutically acceptable salt or solvatethereof, wherein R₇ and R₈ are each halogen. In some embodiments is acompound of Formula (IVd), or a pharmaceutically acceptable salt orsolvate thereof, wherein R₇ and R₈ are each C₁-C₆alkyl. In someembodiments is a compound of Formula (IVd), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₇ is hydrogen and R₈ ishalogen. In some embodiments is a compound of Formula (IVd), or apharmaceutically acceptable salt or solvate thereof, wherein R₇ ishydrogen and R₈ is C₁-C₆alkyl. In some embodiments is a compound ofFormula (IVd), or a pharmaceutically acceptable salt or solvate thereof,wherein R₇ is hydrogen and R₈ is C₁-C₆haloalkyl. In some embodiments isa compound of Formula (IVd), or a pharmaceutically acceptable salt orsolvate thereof, wherein R₇ is hydrogen and R₈ is C₁-C₆alkoxy. In someembodiments is a compound of Formula (IVd), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₇ is hydrogen and R₈ is—CN. In some embodiments is a compound of Formula (IVd), or apharmaceutically acceptable salt or solvate thereof, wherein R₇ ishalogen and R₈ is hydrogen. In some embodiments is a compound of Formula(IVd), or a pharmaceutically acceptable salt or solvate thereof, whereinR₇ is C₁-C₆alkyl and R₈ is hydrogen. In some embodiments is a compoundof Formula (IVd), or a pharmaceutically acceptable salt or solvatethereof, wherein R₇ is C₁-C₆haloalkyl and R₈ is hydrogen. In someembodiments is a compound of Formula (IVd), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₇ is C₁-C₆alkoxy and R₈ ishydrogen. In some embodiments is a compound of Formula (IVd), or apharmaceutically acceptable salt or solvate thereof, wherein R₇ is —CNand R₈ is hydrogen.

In some embodiments is a compound of Formula (IVd), or apharmaceutically acceptable salt or solvate thereof, wherein X is —O—.In some embodiments is a compound of Formula (IVd), or apharmaceutically acceptable salt or solvate thereof, wherein X is —O—and n is 2. In some embodiments is a compound of Formula (IVd), or apharmaceutically acceptable salt or solvate thereof, wherein X is —O—, nis 2, and each R₁ and each R₂ are hydrogen. In some embodiments is acompound of Formula (IVd), or a pharmaceutically acceptable salt orsolvate thereof, wherein X is —O—, n is 2, each R₁ is hydrogen, and oneR₂ is hydrogen and one R₂ is C₁-C₆alkyl. In some embodiments is acompound of Formula (IVd), or a pharmaceutically acceptable salt orsolvate thereof, wherein X is —O— and n is 3. In some embodiments is acompound of Formula (IVd), or a pharmaceutically acceptable salt orsolvate thereof, wherein X is —O—, n is 3, and each R₁ and each R₂ arehydrogen. In some embodiments is a compound of Formula (IVd), or apharmaceutically acceptable salt or solvate thereof, wherein X is —O—, nis 3, one R₁ is C₁-C₆alkyl and one R₂ is C₁-C₆alkyl and the remaining R₁and R₂ are each hydrogen.

In some embodiments is a compound of Formula (IVd), or apharmaceutically acceptable salt or solvate thereof, wherein X is—C(R₉)(R₁₀)—. In some embodiments is a compound of Formula (IVd), or apharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—.In some embodiments is a compound of Formula (IVd), or apharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—and n is 1. In some embodiments is a compound of Formula (IVd), or apharmaceutically acceptable salt or solvate thereof, wherein X is —CH₂—,n is 1, and R₁ and R₂ are hydrogen. In some embodiments is a compound ofFormula (IVd), or a pharmaceutically acceptable salt or solvate thereof,wherein X is —CH₂— and n is 2. In some embodiments is a compound ofFormula (IVd), or a pharmaceutically acceptable salt or solvate thereof,wherein X is —CH₂—, n is 2, and each R₁ and each R₂ are hydrogen. Insome embodiments is a compound of Formula (IVd), or a pharmaceuticallyacceptable salt or solvate thereof, wherein X is —CH₂— and n is 3. Insome embodiments is a compound of Formula (IVd), or a pharmaceuticallyacceptable salt or solvate thereof, wherein X is —CH₂—, n is 3, and eachR₁ and each R₂ are hydrogen.

In some embodiments is a compound of Formula (IVd), or apharmaceutically acceptable salt or solvate thereof, wherein R₄ and R₅are independently selected from hydrogen and C₁-C₆alkyl. In someembodiments is a compound of Formula (IVd), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₄ is hydrogen and R₅ isC₁-C₆alkyl. In some embodiments is a compound of Formula (IVd), or apharmaceutically acceptable salt or solvate thereof, wherein R₄ and R₅are hydrogen. In some embodiments is a compound of Formula (IVd), or apharmaceutically acceptable salt or solvate thereof, wherein R₄ and R₅are C₁-C₆alkyl.

In some embodiments is a compound of Formula (IVd), or apharmaceutically acceptable salt or solvate thereof, wherein R₃ ishydrogen. In some embodiments is a compound of Formula (IVd), or apharmaceutically acceptable salt or solvate thereof, wherein R₃ isC₁-C₆alkyl.

In some embodiments is a compound of Formula (IVd), or apharmaceutically acceptable salt or solvate thereof, wherein R₆ ishydrogen. In some embodiments is a compound of Formula (IVd), or apharmaceutically acceptable salt or solvate thereof, wherein R₆ isC₁-C₆alkyl.

In some embodiments, provided herein is a compound selected from:

or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, provided herein is a compound selected from:

or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, provided herein is a compound selected from:

or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, provided herein is a compound selected from:

or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, provided herein is a compound selected from:

or a pharmaceutically acceptable salt or solvate thereof.

Any combination of the groups described above for the various variablesis contemplated herein. Throughout the specification, groups andsubstituents thereof can be chosen by one skilled in the field toprovide stable moieties and compounds.

In some embodiments, the therapeutic agent(s) (e.g. compound of Formula(I), (II), (III), (IIIa), (IIIb), (IIIc), (IIId), (IV), (IVa), (IVb),(IVc), or (IVd)) is present in the pharmaceutical composition as apharmaceutically acceptable salt. In some embodiments, any compounddescribed above is suitable for any method or composition describedherein.

Further Forms of Compounds Disclosed Herein Isomers

Furthermore, in some embodiments, the compounds described herein existas geometric isomers. In some embodiments, the compounds describedherein possess one or more double bonds. The compounds presented hereininclude all cis, trans, syn, anti, entgegen (E), and zusammen (Z)isomers as well as the corresponding mixtures thereof. In somesituations, compounds exist as tautomers. The compounds described hereininclude all possible tautomers within the formulas described herein. Insome situations, the compounds described herein possess one or morechiral centers and each center exists in the R configuration or Sconfiguration. The compounds described herein include alldiastereomeric, enantiomeric, and epimeric forms as well as thecorresponding mixtures thereof. In additional embodiments of thecompounds and methods provided herein, mixtures of enantiomers and/ordiastereoisomers, resulting from a single preparative step, combination,or interconversion, are useful for the applications described herein. Insome embodiments, the compounds described herein are prepared asoptically pure enantiomers by chiral chromatographic resolution of theracemic mixture. In some embodiments, the compounds described herein areprepared as their individual stereoisomers by reacting a racemic mixtureof the compound with an optically active resolving agent to form a pairof diastereoisomeric compounds, separating the diastereomers, andrecovering the optically pure enantiomers. In some embodiments,dissociable complexes are preferred (e.g., crystalline diastereomericsalts). In some embodiments, the diastereomers have distinct physicalproperties (e.g., melting points, boiling points, solubilities,reactivity, etc.) and are separated by taking advantage of thesedissimilarities. In some embodiments, the diastereomers are separated bychiral chromatography, or preferably, by separation/resolutiontechniques based upon differences in solubility. In some embodiments,the optically pure enantiomer is then recovered, along with theresolving agent, by any practical means that does not result inracemization.

Labeled Compounds

In some embodiments, the compounds described herein exist in theirisotopically-labeled forms. In some embodiments, the methods disclosedherein include methods of treating diseases by administering suchisotopically-labeled compounds. In some embodiments, the methodsdisclosed herein include methods of treating diseases by administeringsuch isotopically-labeled compounds as pharmaceutical compositions.Thus, in some embodiments, the compounds disclosed herein includeisotopically-labeled compounds, which are identical to those recitedherein, but for the fact that one or more atoms are replaced by an atomhaving an atomic mass or mass number different from the atomic mass ormass number usually found in nature. Examples of isotopes that areincorporated into compounds described herein include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, andchloride, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S, ¹⁸F,and ³⁶Cl, respectively. Compounds described herein, and pharmaceuticallyacceptable salts, esters, solvate, hydrates, or derivatives thereofwhich contain the aforementioned isotopes and/or other isotopes of otheratoms are within the scope of this invention. Certainisotopically-labeled compounds, for example those into which radioactiveisotopes such as ³H and ¹⁴C are incorporated, are useful in drug and/orsubstrate tissue distribution assays. Tritiated, i. e., ³H andcarbon-14, i.e., ¹⁴C, isotopes are particularly preferred for their easeof preparation and detectability. Further, substitution with heavyisotopes such as deuterium, i.e., ²H, produces certain therapeuticadvantages resulting from greater metabolic stability, for exampleincreased in vivo half-life or reduced dosage requirements. In someembodiments, the isotopically labeled compounds, pharmaceuticallyacceptable salt, ester, solvate, hydrate, or derivative thereof isprepared by any suitable method.

In some embodiments, the compounds described herein are labeled by othermeans, including, but not limited to, the use of chromophores orfluorescent moieties, bioluminescent labels, or chemiluminescent labels.

Pharmaceutically Acceptable Salts

In some embodiments, the compounds described herein exist as theirpharmaceutically acceptable salts. In some embodiments, the methodsdisclosed herein include methods of treating diseases by administeringsuch pharmaceutically acceptable salts. In some embodiments, the methodsdisclosed herein include methods of treating diseases by administeringsuch pharmaceutically acceptable salts as pharmaceutical compositions.

In some embodiments, the compounds described herein possess acidic orbasic groups and therefore react with any of a number of inorganic ororganic bases, and inorganic and organic acids, to form apharmaceutically acceptable salt. In some embodiments, these salts areprepared in situ during the final isolation and purification of thecompounds described herein, or by separately reacting a purifiedcompound in its free form with a suitable acid or base, and isolatingthe salt thus formed.

Solvates

In some embodiments, the compounds described herein exist as solvates.In some embodiments are methods of treating diseases by administeringsuch solvates. Further described herein are methods of treating diseasesby administering such solvates as pharmaceutical compositions.

Solvates contain either stoichiometric or non-stoichiometric amounts ofa solvent, and, in some embodiments, are formed during the process ofcrystallization with pharmaceutically acceptable solvents such as water,ethanol, and the like. Hydrates are formed when the solvent is water, oralcoholates are formed when the solvent is alcohol. Solvates of thecompounds described herein are conveniently prepared or formed duringthe processes described herein. By way of example only, hydrates of thecompounds described herein are conveniently prepared byrecrystallization from an aqueous/organic solvent mixture, using organicsolvents including, but not limited to, dioxane, tetrahydrofuran, orMeOH. In addition, the compounds provided herein exist in unsolvated aswell as solvated forms. In general, the solvated forms are consideredequivalent to the unsolvated forms for the purposes of the compounds andmethods provided herein.

Synthesis of Compounds

In some embodiments, the synthesis of compounds described herein areaccomplished using means described in the chemical literature, using themethods described herein, or by a combination thereof. In addition,solvents, temperatures and other reaction conditions presented hereinmay vary.

In other embodiments, the starting materials and reagents used for thesynthesis of the compounds described herein are synthesized or areobtained from commercial sources, such as, but not limited to,Sigma-Aldrich, FischerScientific (Fischer Chemicals), and AcrosOrganics.

In further embodiments, the compounds described herein, and otherrelated compounds having different substituents are synthesized usingtechniques and materials described herein as well as those that arerecognized in the field, such as described, for example, in Fieser andFieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley andSons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 andSupplementals (Elsevier Science Publishers, 1989); Organic Reactions,Volumes 1-40 (John Wiley and Sons, 1991), Larock's Comprehensive OrganicTransformations (VCH Publishers Inc., 1989), March, Advanced OrganicChemistry 4^(th) Ed., (Wiley 1992); Carey and Sundberg, Advanced OrganicChemistry 4^(th) Ed., Vols. A and B (Plenum 2000, 2001), and Green andWuts, Protective Groups in Organic Synthesis 3^(rd) Ed., (Wiley 1999)(all of which are incorporated by reference for such disclosure).General methods for the preparation of compound as disclosed herein maybe derived from reactions and the reactions may be modified by the useof appropriate reagents and conditions, for the introduction of thevarious moieties found in the formulae as provided herein. As a guidethe following synthetic methods may be utilized.

Use of Protecting Groups

In the reactions described, it may be necessary to protect reactivefunctional groups, for example hydroxy, amino, imino, thio or carboxygroups, where these are desired in the final product, in order to avoidtheir unwanted participation in reactions. Protecting groups are used toblock some or all of the reactive moieties and prevent such groups fromparticipating in chemical reactions until the protective group isremoved. It is preferred that each protective group be removable by adifferent means. Protective groups that are cleaved under totallydisparate reaction conditions fulfill the requirement of differentialremoval.

Protective groups can be removed by acid, base, reducing conditions(such as, for example, hydrogenolysis), and/or oxidative conditions.Groups such as trityl, dimethoxytrityl, acetal and t-butyldimethylsilylare acid labile and may be used to protect carboxy and hydroxy reactivemoieties in the presence of amino groups protected with Cbz groups,which are removable by hydrogenolysis, and Fmoc groups, which are baselabile. Carboxylic acid and hydroxy reactive moieties may be blockedwith base labile groups such as, but not limited to, methyl, ethyl, andacetyl in the presence of amines blocked with acid labile groups such ast-butyl carbamate or with carbamates that are both acid and base stablebut hydrolytically removable.

Carboxylic acid and hydroxy reactive moieties may also be blocked withhydrolytically removable protective groups such as the benzyl group,while amine groups capable of hydrogen bonding with acids may be blockedwith base labile groups such as Fmoc. Carboxylic acid reactive moietiesmay be protected by conversion to simple ester compounds as exemplifiedherein, which include conversion to alkyl esters, or they may be blockedwith oxidatively-removable protective groups such as2,4-dimethoxybenzyl, while co-existing amino groups may be blocked withfluoride labile silyl carbamates.

Allyl blocking groups are useful in the presence of acid- andbase-protecting groups since the former are stable and can besubsequently removed by metal or pi-acid catalysts. For example, anallyl-blocked carboxylic acid can be deprotected with a Pd⁰-catalyzedreaction in the presence of acid labile t-butyl carbamate or base-labileacetate amine protecting groups. Yet another form of protecting group isa resin to which a compound or intermediate may be attached. As long asthe residue is attached to the resin, that functional group is blockedand cannot react. Once released from the resin, the functional group isavailable to react.

Typically blocking/protecting groups may be selected from:

Other protecting groups, plus a detailed description of techniquesapplicable to the creation of protecting groups and their removal aredescribed in Greene and Wuts, Protective Groups in Organic Synthesis,3rd Ed., John Wiley & Sons, New York, NY, 1999, and Kocienski,Protective Groups, Thieme Verlag, New York, NY, 1994, which areincorporated herein by reference for such disclosure).

Methods of Treatment and Prevention

In some embodiments is a method of treating an inflammatory orautoimmune disease in a patient in need thereof, comprisingadministering to the patient a therapeutically effective amount of acompound Formula (I), (II), (III), (IIIa), (IIIb), (IIIc), (IIId), (IV),(IVa), (IVb), (IVc), or (IVd), or a pharmaceutically acceptable salt orsolvate thereof. In some embodiments is a method of treating aninflammatory disease in a patient in need thereof, comprisingadministering to the patient a therapeutically effective amount of acompound Formula (I), (II), (III), (IIIa), (IIIb), (IIIc), (IIId), (IV),(IVa), (IVb), (IVc), or (IVd), or a pharmaceutically acceptable salt orsolvate thereof. In some embodiments is a method of treating anautoimmune disease in a patient in need thereof, comprisingadministering to the patient a therapeutically effective amount of acompound Formula (I), (II), (III), (IIIa), (IIIb), (IIIc), (IIId), (IV),(IVa), (IVb), (IVc), or (IVd), or a pharmaceutically acceptable salt orsolvate thereof. In some embodiments is a method of treating aninflammatory or autoimmune disease in a patient in need thereof,comprising administering to the patient a therapeutically effectiveamount of a compound Formula (I), (II), (III), (IIIa), (IIIb), (IIIc),(IIId), (IV), (IVa), (IVb), (IVc), or (IVd), or a pharmaceuticallyacceptable salt or solvate thereof, wherein the disease, disorder, orcondition is selected from rheumatoid arthritis, multiple sclerosis,psoriasis, lupus, intestinal bowel disease, Crohn's disease, ulcerativecolitis, ankylosing spondylitis, vitiligo, and atopic dermatitis. Insome embodiments is a method of treating an inflammatory or autoimmunedisease in a patient in need thereof, comprising administering to thepatient a therapeutically effective amount of a compound Formula (I),(II), (III), (IIIa), (IIIb), (IIIc), (IIId), (IV), (IVa), (IVb), (IVc),or (IVd), or a pharmaceutically acceptable salt or solvate thereof,wherein the disease, disorder, or condition is rheumatoid arthritis. Insome embodiments is a method of treating an inflammatory or autoimmunedisease in a patient in need thereof, comprising administering to thepatient a therapeutically effective amount of a compound Formula (I),(II), (III), (IIIa), (IIIb), (IIIc), (IIId), (IV), (IVa), (IVb), (IVc),or (IVd), or a pharmaceutically acceptable salt or solvate thereof,wherein the disease, disorder, or condition is multiple sclerosis. Insome embodiments is a method of treating an inflammatory or autoimmunedisease in a patient in need thereof, comprising administering to thepatient a therapeutically effective amount of a compound Formula (I),(II), (III), (IIIa), (IIIb), (IIIc), (IIId), (IV), (IVa), (IVb), (IVc),or (IVd), or a pharmaceutically acceptable salt or solvate thereof,wherein the disease, disorder, or condition is psoriasis. In someembodiments is a method of treating an inflammatory or autoimmunedisease in a patient in need thereof, comprising administering to thepatient a therapeutically effective amount of a compound Formula (I),(II), (III), (IIIa), (IIIb), (IIIc), (IIId), (IV), (IVa), (IVb), (IVc),or (IVd), or a pharmaceutically acceptable salt or solvate thereof,wherein the disease, disorder, or condition is lupus. In someembodiments is a method of treating an inflammatory or autoimmunedisease in a patient in need thereof, comprising administering to thepatient a therapeutically effective amount of a compound Formula (I),(II), (III), (IIIa), (IIIb), (IIIc), (IIId), (IV), (IVa), (IVb), (IVc),or (IVd), or a pharmaceutically acceptable salt or solvate thereof,wherein the disease, disorder, or condition is intestinal bowel disease.In some embodiments is a method of treating an inflammatory orautoimmune disease in a patient in need thereof, comprisingadministering to the patient a therapeutically effective amount of acompound Formula (I), (II), (III), (IIIa), (IIIb), (IIIc), (IIId), (IV),(IVa), (IVb), (IVc), or (IVd), or a pharmaceutically acceptable salt orsolvate thereof, wherein the disease, disorder, or condition is Crohn'sdisease. In some embodiments is a method of treating an inflammatory orautoimmune disease in a patient in need thereof, comprisingadministering to the patient a therapeutically effective amount of acompound Formula (I), (II), (III), (IIIa), (IIIb), (IIIc), (IIId), (IV),(IVa), (IVb), (IVc), or (IVd), or a pharmaceutically acceptable salt orsolvate thereof, wherein the disease, disorder, or condition isulcerative colitis. In some embodiments is a method of treating aninflammatory or autoimmune disease in a patient in need thereof,comprising administering to the patient a therapeutically effectiveamount of a compound Formula (I), (II), (III), (IIIa), (IIIb), (IIIc),(IIId), (IV), (IVa), (IVb), (IVc), or (IVd), or a pharmaceuticallyacceptable salt or solvate thereof, wherein the disease, disorder, orcondition is ankylosing spondylitis. In some embodiments is a method oftreating an inflammatory or autoimmune disease in a patient in needthereof, comprising administering to the patient a therapeuticallyeffective amount of a compound Formula (I), (II), (III), (IIIa), (IIIb),(IIIc), (IIId), (IV), (IVa), (IVb), (IVc), or (IVd), or apharmaceutically acceptable salt or solvate thereof, wherein thedisease, disorder, or condition is vitiligo. In some embodiments is amethod of treating an inflammatory or autoimmune disease in a patient inneed thereof, comprising administering to the patient a therapeuticallyeffective amount of a compound Formula (I), (II), (III), (IIIa), (IIIb),(IIIc), (IIId), (IV), (IVa), (IVb), (IVc), or (IVd), or apharmaceutically acceptable salt or solvate thereof, wherein thedisease, disorder, or condition is atopic dermatitis.

Pharmaceutical Compositions and Methods of Administration

TYK2 pseudokinase ligands described herein are administered to subjectsin a biologically compatible form suitable for administration to treator prevent diseases, disorders or conditions. Administration of TYK2pseudokinase ligands as described herein can be in any pharmacologicalform including a therapeutically effective amount of a TYK2 pseudokinaseligand alone or in combination with a pharmaceutically acceptablecarrier.

In certain embodiments, the compounds described herein are administeredas a pure chemical. In other embodiments, the compounds described hereinare combined with a pharmaceutically suitable or acceptable carrier(also referred to herein as a pharmaceutically suitable (or acceptable)excipient, physiologically suitable (or acceptable) excipient, orphysiologically suitable (or acceptable) carrier) selected on the basisof a chosen route of administration and standard pharmaceutical practiceas described, for example, in Remington: The Science and Practice ofPharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)).

Accordingly, provided herein is a pharmaceutical composition comprisingat least one compound described herein, or a pharmaceutically acceptablesalt, together with one or more pharmaceutically acceptable carriers.The carrier(s) (or excipient(s)) is acceptable or suitable if thecarrier is compatible with the other ingredients of the composition andnot deleterious to the recipient (i.e., the subject) of the composition.

In some embodiments is a pharmaceutical composition comprising apharmaceutically acceptable carrier and a compound of Formula (I), (II),(III), (IIIa), (IIIb), (IIIc), (IIId), (IV), (IVa), (IVb), (IVc), or(IVd), or a pharmaceutically acceptable salt or solvate thereof. In someembodiments is a pharmaceutical composition comprising apharmaceutically acceptable carrier and a compound of Formula (I), or apharmaceutically acceptable salt or solvate thereof. In some embodimentsis a pharmaceutical composition comprising a pharmaceutically acceptablecarrier and a compound of Formula (Ia), or a pharmaceutically acceptablesalt or solvate thereof. In some embodiments is a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and acompound of Formula (Ib), or a pharmaceutically acceptable salt orsolvate thereof. In some embodiments is a pharmaceutical compositioncomprising a pharmaceutically acceptable carrier and a compound ofFormula (Ic), or a pharmaceutically acceptable salt or solvate thereof.

Another embodiment provides a pharmaceutical composition consistingessentially of a pharmaceutically acceptable carrier and a compound ofFormula (I), (II), (III), (IIIa), (IIIb), (IIIc), (IIId), (IV), (IVa),(IVb), (IVc), or (IVd), or a pharmaceutically acceptable salt or solvatethereof. In some embodiments is a pharmaceutical composition consistingessentially of a pharmaceutically acceptable carrier and a compound ofFormula (I), or a pharmaceutically acceptable salt or solvate thereof.In some embodiments is a pharmaceutical composition consistingessentially of a pharmaceutically acceptable carrier and a compound ofFormula (Ia), or a pharmaceutically acceptable salt or solvate thereof.In some embodiments is a pharmaceutical composition consistingessentially of a pharmaceutically acceptable carrier and a compound ofFormula (Ib), or a pharmaceutically acceptable salt or solvate thereof.In some embodiments is a pharmaceutical composition consistingessentially of a pharmaceutically acceptable carrier and a compound ofFormula (Ic), or a pharmaceutically acceptable salt or solvate thereof.

In certain embodiments, the compound as described herein issubstantially pure, in that it contains less than about 5%, or less thanabout 1%, or less than about 0.1%, of other organic small molecules,such as contaminating intermediates or by-products that are created, forexample, in one or more of the steps of a synthesis method.

These formulations include those suitable for oral, topical, buccal,parenteral (e.g., subcutaneous, intramuscular, intradermal, orintravenous), or aerosol administration.

Exemplary pharmaceutical compositions are used in the form of apharmaceutical preparation, for example, in solid, semisolid or liquidform, which includes one or more of a disclosed compound, as an activeingredient, in a mixture with an organic or inorganic carrier orexcipient suitable for external, enteral or parenteral applications. Insome embodiments, the active ingredient is compounded, for example, withthe usual non-toxic, pharmaceutically acceptable carriers for tablets,pellets, capsules, suppositories, solutions, emulsions, suspensions, andany other form suitable for use. The active object compound is includedin the pharmaceutical composition in an amount sufficient to produce thedesired effect upon the process or condition of the disease.

In some embodiments, TYK2 pseudokinase ligands described herein areadministered to subjects in a biologically compatible form suitable fortopical administration to treat or prevent dermal diseases, disorders orconditions. By “biologically compatible form suitable for topicaladministration” is meant a form of the TYK2 pseudokinase ligand to beadministered in which any toxic effects are outweighed by thetherapeutic effects of the inhibitor. Administration of TYK2pseudokinase ligands as described herein can be in any pharmacologicalform including a therapeutically effective amount of a TYK2 pseudokinaseligand alone or in combination with a pharmaceutically acceptablecarrier.

Topical administration of a TYK2 pseudokinase ligand may be presented inthe form of an aerosol, a semi-solid pharmaceutical composition, apowder, or a solution. By the term “a semi-solid composition” is meantan ointment, cream, salve, jelly, or other pharmaceutical composition ofsubstantially similar consistency suitable for application to the skin.Examples of semi-solid compositions are given in Chapter 17 of TheTheory and Practice of Industrial Pharmacy, Lachman, Lieberman andKanig, published by Lea and Febiger (1970) and in Chapter 67 ofRemington's Pharmaceutical Sciences, 15th Edition (1975) published byMack Publishing Company.

Dermal or skin patches are another method for transdermal delivery ofthe therapeutic or pharmaceutical compositions described herein. Patchescan provide an absorption enhancer such as DMSO to increase theabsorption of the compounds. Patches can include those that control therate of drug delivery to the skin. Patches may provide a variety ofdosing systems including a reservoir system or a monolithic system,respectively. The reservoir design may, for example, have four layers:the adhesive layer that directly contacts the skin, the controlmembrane, which controls the diffusion of drug molecules, the reservoirof drug molecules, and a water-resistant backing. Such a design deliversuniform amounts of the drug over a specified time period, the rate ofdelivery has to be less than the saturation limit of different types ofskin. The monolithic design, for example, typically has only threelayers: the adhesive layer, a polymer matrix containing the compound,and a water-proof backing. This design brings a saturating amount ofdrug to the skin. Thereby, delivery is controlled by the skin. As thedrug amount decreases in the patch to below the saturating level, thedelivery rate falls.

In one embodiment, the topical composition may, for example, take theform of hydrogel based on polyacrylic acid or polyacrylamide; as anointment, for example with polyethyleneglycol (PEG) as the carrier, likethe standard ointment DAB 8 (50% PEG 300, 50% PEG 1500); or as anemulsion, especially a microemulsion based on water-in-oil oroil-in-water, optionally with added liposomes. Suitable permeationaccelerators (entraining agents) include sulphoxide derivatives such asdimethylsulfoxide (DMSO) or decylmethylsulfoxide (decyl-MSO) andtranscutol (diethyleneglycolmonoethylether) or cyclodextrin; as well aspyrrolidones, for example 2-pyrrolidone, N-methyl-2-pyrrolidone,2-pyrrolidone-5-carboxylic acid, or the biodegradableN-(2-hydroxyethyl)-2-pyrrolidone and the fatty acid esters thereof; ureaderivatives such as dodecylurea, 1,3-didodecylurea, and1,3-diphenylurea; terpenes, for example D-limonene, menthone,a-terpinol, carvol, limonene oxide, or 1,8-cineol.

Ointments, pastes, creams and gels also can contain excipients, such asstarch, tragacanth, cellulose derivatives, polyethylene glycols,silicones, bentonites, silicic acid, and talc, or mixtures thereof.Powders and sprays also can contain excipients such as lactose, talc,silicic acid, aluminum hydroxide, calcium silicates and polyamidepowder, or mixtures of these substances. Solutions of nanocrystallineantimicrobial metals can be converted into aerosols or sprays by any ofthe known means routinely used for making aerosol pharmaceuticals. Ingeneral, such methods comprise pressurizing or providing a means forpressurizing a container of the solution, usually with an inert carriergas, and passing the pressurized gas through a small orifice. Sprays canadditionally contain customary propellants, such achlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, suchas butane and propane.

The carrier can also contain other pharmaceutically-acceptableexcipients for modifying or maintaining the pH, osmolarity, viscosity,clarity, color, sterility, stability, rate of dissolution, or odor ofthe formulation. The anti-skin aging compositions can also furthercomprise antioxidants, sun screens, natural retinoids (e.g., retinol),and other additives commonly found in skin treatment compositions.

In some embodiments for preparing solid compositions such as tablets,the principal active ingredient is mixed with a pharmaceutical carrier,e.g., conventional tableting ingredients such as corn starch, lactose,sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalciumphosphate or gums, and other pharmaceutical diluents, e.g., water, toform a solid preformulation composition containing a homogeneous mixtureof a disclosed compound or a non-toxic pharmaceutically acceptable saltthereof. When referring to these preformulation compositions ashomogeneous, it is meant that the active ingredient is dispersed evenlythroughout the composition so that the composition is readily subdividedinto equally effective unit dosage forms such as tablets, pills andcapsules.

In solid dosage forms for oral administration (capsules, tablets, pills,dragees, powders, granules and the like), the subject composition ismixed with one or more pharmaceutically acceptable carriers, such assodium citrate or dicalcium phosphate, and/or any of the following: (1)fillers or extenders, such as starches, cellulose, microcrystallinecellulose, silicified microcrystalline cellulose, lactose, sucrose,glucose, mannitol, and/or silicic acid; (2) binders, such as, forexample, carboxymethylcellulose, hypromellose, alginates, gelatin,polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such asglycerol; (4) disintegrating agents, such as crospovidone,croscarmellose sodium, sodium starch glycolate, agar-agar, calciumcarbonate, potato or tapioca starch, alginic acid, certain silicates,and sodium carbonate; (5) solution retarding agents, such as paraffin;(6) absorption accelerators, such as quaternary ammonium compounds; (7)wetting agents, such as, for example, docusate sodium, cetyl alcohol andglycerol monostearate; (8) absorbents, such as kaolin and bentoniteclay; (9) lubricants, such a talc, calcium stearate, magnesium stearate,solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof,and (10) coloring agents. In the case of capsules, tablets and pills, insome embodiments, the compositions comprise buffering agents. In someembodiments, solid compositions of a similar type are also employed asfillers in soft and hard-filled gelatin capsules using such excipientsas lactose or milk sugars, as well as high molecular weight polyethyleneglycols and the like.

In some embodiments, a tablet is made by compression or molding,optionally with one or more accessory ingredients. In some embodiments,compressed tablets are prepared using binder (for example, gelatin orhydroxypropylmethyl cellulose), lubricant, inert diluent, preservative,disintegrant (for example, sodium starch glycolate or cross-linkedsodium carboxymethyl cellulose), surface-active or dispersing agent. Insome embodiments, molded tablets are made by molding in a suitablemachine a mixture of the subject composition moistened with an inertliquid diluent. In some embodiments, tablets, and other solid dosageforms, such as dragees, capsules, pills and granules, are scored orprepared with coatings and shells, such as enteric coatings and othercoatings.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. Liquid dosage forms for oraladministration include pharmaceutically acceptable emulsions,microemulsions, solutions, suspensions, syrups and elixirs. In additionto the subject composition, in some embodiments, the liquid dosage formscontain inert diluents, such as, for example, water or other solvents,solubilizing agents and emulsifiers, such as ethyl alcohol, isopropylalcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzylbenzoate, propylene glycol, 1,3-butylene glycol, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor and sesame oils),glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acidesters of sorbitan, cyclodextrins and mixtures thereof.

In some embodiments, suspensions, in addition to the subjectcomposition, contain suspending agents as, for example, ethoxylatedisostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters,microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agarand tragacanth, and mixtures thereof.

In some embodiments, powders and sprays contain, in addition to asubject composition, excipients such as lactose, talc, silicic acid,aluminum hydroxide, calcium silicates and polyamide powder, or mixturesof these substances. In some embodiments, sprays additionally containcustomary propellants, such as chlorofluorohydrocarbons and volatileunsubstituted hydrocarbons, such as butane and propane.

Compositions and compounds disclosed herein alternatively areadministered by aerosol. This is accomplished by preparing an aqueousaerosol, liposomal preparation or solid particles containing thecompound. In some embodiments, a non-aqueous (e.g., fluorocarbonpropellant) suspension is used. In some embodiments, sonic nebulizersare used because they minimize exposing the agent to shear, whichresults in degradation of the compounds contained in the subjectcompositions. Ordinarily, an aqueous aerosol is made by formulating anaqueous solution or suspension of a subject composition together withconventional pharmaceutically acceptable carriers and stabilizers. Thecarriers and stabilizers vary with the requirements of the particularsubject composition, but typically include non-ionic surfactants(Tweens, Pluronics, or polyethylene glycol), innocuous proteins likeserum albumin, sorbitan esters, oleic acid, lecithin, amino acids suchas glycine, buffers, salts, sugars or sugar alcohols. Aerosols generallyare prepared from isotonic solutions.

Pharmaceutical compositions suitable for parenteral administrationcomprise a subject composition in combination with one or morepharmaceutically-acceptable sterile isotonic aqueous or non-aqueoussolutions, dispersions, suspensions or emulsions, or sterile powderswhich are reconstituted into sterile injectable solutions or dispersionsjust prior to use, which, in some embodiments, contain antioxidants,buffers, bacteriostats, solutes which render the formulation isotonicwith the blood of the intended recipient or suspending or thickeningagents.

Examples of suitable aqueous and non-aqueous carriers which are employedin the pharmaceutical compositions include water, ethanol, polyols (suchas glycerol, propylene glycol, polyethylene glycol, and the like), andsuitable mixtures thereof, vegetable oils, such as olive oil, andinjectable organic esters, such as ethyl oleate and cyclodextrins.Proper fluidity is maintained, for example, by the use of coatingmaterials, such as lecithin, by the maintenance of the required particlesize in the case of dispersions, and by the use of surfactants.

The dose of the composition comprising at least one compound describedherein differs, depending upon the patient's (e.g., human) condition,that is, stage of the disease, general health status, age, and otherfactors.

Pharmaceutical compositions are administered in a manner appropriate tothe disease to be treated (or prevented). An appropriate dose and asuitable duration and frequency of administration will be determined bysuch factors as the condition of the patient, the type and severity ofthe patient's disease, the particular form of the active ingredient, andthe method of administration. In general, an appropriate dose andtreatment regimen provides the composition(s) in an amount sufficient toprovide therapeutic and/or prophylactic benefit (e.g., an improvedclinical outcome, such as more frequent complete or partial remissions,or longer disease-free and/or overall survival, or a lessening ofsymptom severity). Optimal doses are generally determined usingexperimental models and/or clinical trials. In some embodiments, theoptimal dose depends upon the body mass, weight, or blood volume of thepatient.

Oral doses typically range from about 1.0 mg to about 1000 mg, one tofour times, or more, per day.

Dose administration can be repeated depending upon the pharmacokineticparameters of the dosage formulation and the route of administrationused.

It is especially advantageous to formulate compositions in dosage unitform for ease of administration and uniformity of dosage. Dosage unitform as used herein refers to physically discrete units suited asunitary dosages for the mammalian subjects to be treated; each unitcontaining a predetermined quantity of active compound calculated toproduce the desired therapeutic effect in association with the requiredpharmaceutical carrier. The specification for the dosage unit forms aredictated by and directly dependent on (a) the unique characteristics ofthe TYK2 pseudokinase ligand and the particular therapeutic effect to beachieved and (b) the limitations inherent in the art of compounding suchan active compound for the treatment of sensitivity in individuals. Thespecific dose can be readily calculated by one of ordinary skill in theart, e.g., according to the approximate body weight or body surface areaof the patient or the volume of body space to be occupied. The dose willalso be calculated dependent upon the particular route of administrationselected. Further refinement of the calculations necessary to determinethe appropriate dosage for treatment is routinely made by those ofordinary skill in the art. Such calculations can be made without undueexperimentation by one skilled in the art in light of the TYK2pseudokinase ligand activities disclosed herein in assay preparations oftarget cells. Exact dosages are determined in conjunction with standarddose-response studies. It will be understood that the amount of thecomposition actually administered will be determined by a practitioner,in the light of the relevant circumstances including the condition orconditions to be treated, the choice of composition to be administered,the age, weight, and response of the individual patient, the severity ofthe patient's symptoms, and the chosen route of administration.

Toxicity and therapeutic efficacy of such TYK2 pseudokinase ligands canbe determined by standard pharmaceutical procedures in cell cultures orexperimental animals, for example, for determining the LD₅₀ (the doselethal to 50% of the population) and the ED₅₀ (the dose therapeuticallyeffective in 50% of the population). The dose ratio between toxic andtherapeutic effects is the therapeutic index and it can be expressed asthe ratio LD₅₀/ED₅₀. TYK2 pseudokinase ligands that exhibit largetherapeutic indices are preferred. While TYK2 pseudokinase ligands thatexhibit toxic side effects may be used, care should be taken to design adelivery system that targets such inhibitors to the site of affectedtissue in order to minimize potential damage to uninfected cells and,thereby, reduce side effects.

The data obtained from the cell culture assays and animal studies can beused in formulating a range of dosage for use in humans. The dosage ofsuch TYK2 pseudokinase ligands lies preferably within a range ofcirculating concentrations that include the ED₅₀ with little or notoxicity. The dosage may vary within this range depending upon thedosage form employed and the route of administration utilized. For anyTYK2 pseudokinase ligand used in a method described herein, thetherapeutically effective dose can be estimated initially from cellculture assays. A dose may be formulated in animal models to achieve acirculating plasma concentration range that includes the IC₅₀ (i.e., theconcentration of TYK2 pseudokinase ligand that achieves a half-maximalinhibition of symptoms) as determined in cell culture. Such informationcan be used to more accurately determine useful doses in humans. Levelsin plasma may be measured, for example, by high performance liquidchromatography.

EXAMPLES

The following examples are offered for purposes of illustration and arenot intended to limit the scope of the claims provided herein. Allliterature citations in these examples and throughout this specificationare incorporated herein by references for all legal purposes to beserved thereby. The starting materials and reagents used for thesynthesis of the compounds described herein may be synthesized or can beobtained from commercial sources, such as, but not limited to,Sigma-Aldrich, Acros Organics, Fluka, and Fischer Scientific.

Standard abbreviations and acronyms as defined in J. Org. Chem. 200772(1): 23A-24A are used herein. Other abbreviations and acronyms usedherein are as follows:

AcOH acetic acid DMF dimethylformamide DMP Dess-Martin periodinane dppf(diphenylphosphino)ferrocene EtOAc ethyl acetate EtOH ethanol eqequivalent HBTU N,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1- yl)uroniumhexafluorophosphate LC-MS liquid chromatography-mass spectrometry MeOHmethanol TEA triethylamine rt room temperature

Example 1: Synthesis of(1³E,1⁴E)-1⁷-(methylamino)-4-oxa-2,7-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidina-3(1,3)-benzenacyclooctaphan-8-one(7)

To a stirred solution of 3-nitrophenol (5.0 g, 35.97 mmol) in DMF (100mL) under inert atmosphere were added potassium carbonate (7.44 g, 53.95mmol) and tert-butyl (2-bromoethyl) carbamate (8.02 g, 35.97 mmol) atroom temperature. The reaction mixture was stirred at 50° C. for 16 h.The reaction mixture was then diluted with water (100 mL) and extractedwith EtOAc (2×100 mL). The combined organic extracts were washed withbrine (100 mL), dried over anhydrous Na₂SO₄, filtered, and concentratedunder reduced pressure. The residue was purified by silica gel flashcolumn chromatography to afford tert-butyl(2-(3-nitrophenoxy)ethyl)carbamate (1) (2.0 g, 20%) as a pale yellowsemisolid. ¹H NMR (400 MHz, CDCl₃): δ 7.84 (dd, J=8.1, 1.3 Hz, 1H), 7.73(t, J=2.1 Hz, 1H), 7.44 (t, J=8.2 Hz, 1H), 7.23 (dd, J=8.3, 2.4 Hz, 1H),4.96 (br s, 1H), 4.10 (t, J=5.2 Hz, 2H), 3.60-3.56 (m, 2H), 1.46 (s,9H).

To a stirred solution of tert-butyl (2-(3-nitrophenoxy)ethyl)carbamate(1) (2.0 g, 7.09 mmol) in MeOH (30 mL) under inert atmosphere was added10% Pd/C (600 mg, 50% wet) at room temperature. The reaction mixture wasstirred at room temperature under hydrogen atmosphere for 4 h. Thereaction mixture was filtered through a celite pad and washed with MeOH(100 mL). The filtrate was concentrated under reduced pressure to obtaintert-butyl (2-(3-aminophenoxy)ethyl)carbamate (2) (1.6 g, 90%) as abrown syrup. ¹H NMR (400 MHz, DMSO-d₆). δ 6.97-6.92 (m, 1H), 6.88 (t,J=7.9 Hz, 1H), 6.17-6.10 (m, 2H), 6.06 (dd, J=8.1, 1.7 Hz, 1H), 5.01 (s,2H), 3.82 (t, J=5.9 Hz, 2H), 3.28-3.11 (m, 2H), 1.38 (s, 9H).

To a stirred solution of ethyl5-chloro-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxylate (3) (750mg, 2.95 mmol) in 1,4-dioxane (15 mL) under inert atmosphere were addedtert-butyl (2-(3-aminophenoxy) ethyl) carbamate (2) (1.11 g, 4.42 mmol)and cesium carbonate (1.91 g, 5.90 mmol) at room temperature. Thereaction mixture was purged under argon for 5 min. Then Pd(OAc)₂ (172mg, 0.76 mmol) and (±) BINAP (734 mg, 1.18 mmol) were added to thereaction mixture at room temperature. The reaction mixture was stirredat 110° C. for 16 h in a sealed tube. The reaction mixture was filteredthrough celite and the filtrate was concentrated under reduced pressure.The crude was purified by silica gel flash column chromatography toafford ethyl5-((3-(2-((tert-butoxycarbonyl)amino)ethoxy)phenyl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxylate(4) (800 mg, 58%) as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ9.44 (s, 1H), 8.24 (s, 1H), 7.82 (s, 1H), 7.80-7.76 (m, 1H), 7.47 (dd,J=8.1, 1.0 Hz, 1H), 7.15 (t, J=8.2 Hz, 1H), 6.94 (t, J=5.1 Hz, 1H), 6.53(dd, J=8.2, 2.0 Hz, 1H), 5.58 (s, 1H), 4.29-4.24 (m, 2H), 4.00 (t, J=5.8Hz, 2H), 3.32-3.28 (m, 2H), 2.90 (d, J=4.8 Hz, 3H), 1.38 (s, 9H), 1.35(t, J=7.1 Hz, 3H).

To a stirred solution of ethyl5-((3-(2-((tert-butoxycarbonyl)amino)ethoxy)phenyl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxylate(4) (700 mg, 1.48 mmol) in EtOH (32 mL) under inert atmosphere was addedsodium hydroxide (5 mL, 2.0N in H₂O) at room temperature. The reactionmixture was stirred at 80° C. for 2 h. The reaction mixture was thenacidified with 2.0N HCl solution and extracted with EtOAc (2×30 mL). Thecombined organic extracts were dried over anhydrous Na₂SO₄, filtered,and concentrated under reduced pressure to obtain5-((3-(2-((tert-butoxycarbonyl)amino)ethoxy)phenyl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (5) (650 g, 98%) as an off-white solid. ¹H NMR (500 MHz, DMSO-d₆):δ 11.69 (br s, 1H), 9.45 (s, 1H), 8.21 (s, 1H), 8.08 (br s, 1H), 7.77(d, J=4.6 Hz, 1H), 7.18-7.09 (m, 2H), 6.93-6.89 (m, 1H), 6.50 (d, J=7.5Hz, 1H), 5.59 (s, 1H), 4.00 (t, J=5.5 Hz, 2H), 3.32-3.28 (m, 2H), 2.90(d, J=4.6 Hz, 3H), 1.38 (s, 9H).

To a stirred solution of5-((3-(2-((tert-butoxycarbonyl)amino)ethoxy)phenyl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (5) (750 mg, 1.70 mmol) in CH₂Cl₂ (21 mL) under inert atmospherewas added HCl (10 mL, 4.0 Min 1, 4-dioxane) at 0° C. The reactionmixture was stirred at room temperature for 2 h. Volatiles wereevaporated under reduced pressure. The residue was washed with ether(2×25 mL) and EtOAc (2×25 mL) to obtain5-((3-(2-aminoethoxy)phenyl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid hydrochloride (6) (500 mg, 78%) as an off-white solid. ¹H NMR (400MHz, DMSO-d₆): δ 10.03 (br s, 1H), 8.33-8.22 (m, 4H), 8.14 (br s, 2H),7.29-7.14 (m, 1H), 7.06 (d, J=7.9 Hz, 1H), 6.64 (d, J=7.1 Hz, 1H), 5.68(s, 1H), 4.25 (t, J=5.0 Hz, 2H), 3.28-3.16 (m, 2H), 2.91 (s, 3H).

To a stirred solution5-((3-(2-aminoethoxy)phenyl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid hydrochloride (6) (550 mg, 1.45 mmol) in CH₂Cl₂ (75 mL) under inertatmosphere were added EDCI·HCl (556 mg, 2.91 mmol) and pentafluorophenol(535 mg, 2.91 mmol) at 0° C. The reaction mixture was stirred at roomtemperature for 2 h. Volatiles were evaporated under reduced pressure.The residue was co-distilled with n-pentane (20 mL) and concentratedunder reduced pressure. To a solution of the residue in CH₃CN (15.0 mL)at 70° C. was added diisopropyl ethyl amine (3 mL, 17.46 mmol) in CH₃CN(94 mL) dropwise at 70° C. The reaction mixture was stirred at 70° C.for 3 h. The reaction mixture was diluted with saturated ammoniumchloride solution (100 mL) and extracted with EtOAc (2×100 mL). Thecombined organic extracts were washed with 1N HCl solution (30 mL),water (30 mL), brine (30 mL), dried over anhydrous Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified by silicagel flash column chromatography to afford(1³E,1⁴E)-1⁷-(methylamino)-4-oxa-2,7-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidina-3(1,3)-benzenacyclooctaphan-8-one(7) (25 mg, 5%) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 9.73(t, J=4.6 Hz, 1H), 9.66 (s, 1H), 8.10 (s, 1H), 8.01-7.93 (m, 2H), 7.18(t, J=8.0 Hz, 1H), 6.66-6.57 (m, 2H), 5.42 (s, 1H), 4.52-4.38 (m, 2H),3.61 (br s, 2H), 2.93 (d, J=4.8 Hz, 3H); LCMS: 99.28%; 325.2 (M+H)⁺.

Example 2: Synthesis of(E)-1⁸-(methylamino)-4-oxa-2,7-diaza-1(6,3)-imidazo[1,2-b]pyridazina-3(1,3)-benzenacyclooctaphan-8-one(12)

To a stirred solution of ethyl6-chloro-8-((4-methoxybenzyl)(methyl)amino)imidazo[1,2-b]pyridazine-3-carboxylate(8) (1.2 g, 3.20 mmol) in 1,4-dioxane (24 mL) under inert atmospherewere added tert-butyl (2-(3-aminophenoxy) ethyl) carbamate (2) (970 mg,3.85 mmol) and potassium carbonate (885 mg, 6.41 mmol) at roomtemperature. The reaction mixture was purged under argon for 5 min. ThenPd(OAc)₂ (144 mg, 0.64 mmol) and brettphos (344 mg, 0.64 mmol) wereadded to the reaction mixture at room temperature. The reaction mixturewas stirred at 110° C. for 2 h in a sealed tube. The reaction mixturewas diluted with water (100 mL) and extracted with EtOAc (2×100 mL). Thecombined organic extracts were washed with water (100 mL), dried overanhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. Theresidue was purified by silica gel flash column chromatography to affordethyl6-((3-(2-((tert-butoxycarbonyl)amino)ethoxy)phenyl)amino)-8-((4-methoxybenzyl)(methyl)amino)imidazo[1,2-b]pyridazine-3-carboxylate(9) (1.5 g, 2.54 mmol, 79%) as a pale yellow solid. ¹H NMR (400 MHz,DMSO-d₆): δ 9.07 (s, 1H), 8.02 (s, 1H), 7.79 (s, 1H), 7.26 (d, J=8.2 Hz,1H), 7.18-7.12 (m, 3H), 6.95-6.92 (m, 1H), 6.87 (d, J=8.7 Hz, 2H), 6.48(dd, J=7.9, 1.8 Hz, 1H), 5.97 (s, 1H), 5.39 (s, 2H), 4.43-4.38 (m, 2H),4.04 (t, J=5.7 Hz, 2H), 3.71 (s, 3H), 3.35-3.27 (m, 2H), 3.06 (s, 3H),1.42-1.31 (m, 12H).

To a stirred solution of ethyl6-((3-(2-((tert-butoxycarbonyl)amino)ethoxy)phenyl)amino)-8-((4-methoxybenzyl)(methyl)amino)imidazo[1,2-b]pyridazine-3-carboxylate(9) (1.5 g, 2.54 mmol) in EtOH (45 mL) under inert atmosphere was addedsodium hydroxide (7.5 mL, 2.0N in water) at 0° C. The reaction mixturewas stirred at 80° C. for 90 min. The reaction mixture was thenacidified with 2 N HCl solution and concentrated under reduced pressure.The residue was extracted with EtOAc (2×100 mL). The combined organicextracts were dried over anhydrous Na₂SO₄, filtered, and concentratedunder reduced pressure to obtain6-((3-(2-((tert-butoxycarbonyl)amino)ethoxy)phenyl)amino)-8-((4-methoxybenzyl)(methyl)amino)imidazo[1,2-b]pyridazine-3-carboxylicacid (10) (1.2 g, 2.13 mmol, 84%) as an off-white solid. ¹H NMR (400MHz, DMSO-d₆): δ 12.74 (br s, 1H), 9.06 (s, 1H), 7.99 (s, 1H), 7.68 (s,1H), 7.24-7.08 (m, 4H), 6.92 (t, J=4.8 Hz, 1H), 6.88 (d, J=8.68 Hz, 2H),6.48 (dd, J=8.1, 1.6 Hz, 1H), 5.95 (s, 1H), 5.39 (s, 2H), 4.02 (t, J=5.6Hz, 2H), 3.71 (s, 3H), 3.32-3.30 (m, 2H), 3.07 (s, 3H), 1.38 (s, 9H).

To a stirred solution of6-((3-(2-((tert-butoxycarbonyl)amino)ethoxy)phenyl)amino)-8-((4-methoxybenzyl)(methyl)amino)imidazo[1,2-b]pyridazine-3-carboxylicacid (10) (1.0 g, 1.77 mmol) in CH₂Cl₂ (20 mL) under inert atmospherewas added HCl (10 mL, 4.0 Min 1, 4-dioxane) at 0° C. The reactionmixture was stirred at room temperature for 16 h. Volatiles wereevaporated under reduced pressure. The residue was washed with ether(2×25 mL) and EtOAc (2×25 mL) to obtain6-((3-(2-aminoethoxy)phenyl)amino)-8-(methylamino)imidazo[1,2-b]pyridazine-3-carboxylicacid (11) (650 mg, crude) as an off-white solid. ¹H NMR (400 MHz,DMSO-d₆): δ 9.44 (s, 1H), 8.22-8.18 (m, 4H), 7.98 (s, 1H), 7.70-7.65 (m,1H), 7.30-7.13 (m, 2H), 6.55 (d, J=7.8 Hz, 1H), 6.05 (s, 1H), 4.27 (t,J=4.8 Hz, 2H), 3.25-3.18 (m, 2H), 2.89 (s, 3H).

To a stirred solution6-((3-(2-aminoethoxy)phenyl)amino)-8-(methylamino)imidazo[1,2-b]pyridazine-3-carboxylicacid (11) (550 mg, 1.60 mmol) in CH₂Cl₂:DMF (4:1) (55 mL) under inertatmosphere were added FDDP (803 mg, 2.09 mmol) and diisopropyl ethylamine (2.24 mL, 12.86 mmol) at room temperature. The reaction mixturewas stirred at 70° C. for 1 h. The reaction mixture was quenched with2.0M sodium carbonate solution (150 mL) and extracted with EtOAc (2×100mL). The combined organic extracts were washed with water (100 mL),brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentratedunder reduced pressure. The crude was purified by silica gel flashcolumn chromatography to afford(E)-1⁸-(methylamino)-4-oxa-2,7-diaza-1(6,3)-imidazo[1,2-b]pyridazina-3(1,3)-benzenacyclooctaphan-8-one(12) (14 mg, 3%) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆): δ10.36 (t, J=4.8 Hz, 1H), 9.21 (s, 1H), 7.87 (s, 1H), 7.78 (s, 1H), 7.58(d, J=4.9 Hz, 1H), 7.18 (t, J=8.1 Hz, 1H), 6.63 (d, J=7.6 Hz, 1H), 6.58(dd, J=8.3, 2.0 Hz, 1H), 5.70 (s, 1H), 4.57-4.43 (m, 2H), 3.71-3.67 (m,2H), 2.89 (d, J=4.8 Hz, 3H); LCMS: 94.74%; 325.3 (M+H)⁺.

Compounds 13-47 were prepared by similar procedures as described in thepreceding Examples.

MS Compound Structure Name [M + H]⁺ 13

(1³E,1⁴E)-4,4-dimethyl-1⁷- (methylamino)-2,6-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidina- 3(1,3)-benzenacycloheptaphan- 7-one 337.3 14

(1³E,1⁴E)-1⁷-((methyl- d₃)amino)-4-oxa-2,7-diaza- 1(5,3)-pyrazolo[1,5-a]pyrimidina-3(1,3)- benzenacyclooctaphan-8-one 328.4 15

(1³E,1⁴E)-1⁷-(methylamino)-4- oxa-2,7-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidina- 3(1,3)-benzenacyclooctaphn-8- one-5,5,6,6-d4329.3 16

(1³E,1⁴E)-1⁷-(methylamino)-2,6- diaza-1(5,3)-pyrazolo[1,5-a]pyrimidina-3(1,3)- benzenacycloheptaphan-7-one 309.0 17

(1³E,1⁴E)-1⁷-(methylamino)-4- oxa-2,7-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidina- 3(2,6)-pyridinacyclooctaphan-8- one 326.4 18

(1³E,1⁴E)-1⁷-(methylamino)-2,7- diaza-1(5,3)-pyrazolo[1,5-a]pyrimidina-3(1,3)- benzenacyclooctaphan-8-one 323.6 19

(1³E,1⁴E)-3⁵-fluoro-1⁷- (methylamino)-4-oxa-2,7-diaza-1(5,3)-pyrazolo[1,5- a]pyrimidina-3(1,3)- benzenacyclooctaphan-8-one343.2 20

(1³E,1⁴E)-1⁷-(methylamino)-4- oxa-2,7-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidina- 3(1,2)-benzenacyclooctaphan-8- one 324.5 21

(1³E,1⁴E)-3⁴-fluoro-1⁷- (methylamino)-4-oxa-2,7-diaza-1(5,3)-pyrazolo[1,5- a]pyrimidina-3(1,3)- benzenacyclooctaphan-8-one343.3 22

(1³E,1⁴E)-3⁶-fluoro-1⁷- (methylamino)-4-oxa-2,7-diaza-1(5,3)-pyrazolo[1,5- a]pyrimidina-3(1,3)- benzenacyclooctaphan-8-one343.2 23

(1³E,1⁴E)-3⁴-chloro-1⁷- (methylamino)-4-oxa-2,7-diaza-1(5,3)-pyrazolo[1,5- a]pyrimidina-3(1,3)- benzenacyclooctaphan-8-one359.3 24

(1³E,1⁴E)-1⁷-((methyl- d3)amino)-2,7-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidina- 3(1,3)-benzenacyclooctaphan-8- one 326.3 25

(1³E,1⁴E)-6-methyl-1⁷- (methylamino)-4-oxa-2,7-diaza-1(5,3)-pyrazolo[1,5- a]pyrimidina-3(1,3)- benzenacyclooctaphan-8-one339.5 26

(1³E,1⁴E)-3⁵-methyl-1⁷- (methylamino)-4-oxa-2,7-diaza-1(5,3)-pyrazolo[1,5- a]pyrimidina-3(1,3)- benzenacyclooctaphan-8-one339.3 27

(1³E,1⁴E)-3⁴,3⁶-dichloro-1⁷- (methylamino)-4-oxa-2,7-diaza-1(5,3)-pyrazolo[1,5- a]pyrimidina-3(1,3)- benzenacyclooctaphan-8-one394.3 28

(1³E,1⁴E)-3⁴,3⁵-difluoro-1⁷- (methylamino)-4-oxa-2,7-diaza-1(5,3)-pyrazolo[1,5- a]pyrimidina-3(1,3)- benzenacyclooctaphan-8-one361.3 29

(1⁵E,1⁴E)-3⁴,3⁶-difluoro-1⁷- (methylamino)-4-oxa-2,7-diaza-1(5,3)-pyrazolo[1,5- a]pyrimidina-3(1,3)- benzenacyclooctaphan-8-one361.2 30

(1³E,1⁴E)-5-methyl-1⁷- (methylamino)-4-oxa-2,7-diaza-1(5,3)-pyrazolo[1,5- a]pyrimidina-3(1,2)- benzenacyclooctaphan-8-one339.5 31

(1³E,1⁴E)-3⁴-methoxy-1⁷- (methylamino)-4-oxa-2,7-diaza-1(5,3)-pyrazolo[1,5- a]pyrimidina-3(1,3)- benzenacyclooctaphan-8-one355.4 32

(1³E,1⁴E)-3⁵-fluoro-1⁷- (methylamino)-4-oxa-2,7-diaza-1(5,3)-pyrazolo[1,5- a]pyrimidina-3(1,2)- benzenacyclooctaphan-8-one343.3 33

(1³E,1⁴E)-3⁵-chloro-1⁷- (methylamino)-4-oxa-2,7-diaza-1(5,3)-pyrazolo[1,5- a]pyrimidina-3(1,3)- benzenacyclooctaphan-8-one359.8 34

(1³E,1⁴E)-3⁴-fluoro-1⁷- (methylamino)-4-oxa-2,7-diaza-1(5,3)-pyrazolo[1,5- a]pyrimidina-3(1,2)- benzenacyclooctaphan-8-one342.4 35

(1³E,1⁴E)-1⁷-(methylamino)-4- oxa-2,9-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidina- 3(1,3)-benzenacyclodecaphan- 10-one 353.1 36

(1³E,1⁴E)-6-methyl-1⁷- (methylamino)-4-oxa-2,7-diaza-1(5,3)-pyrazolo[1,5- a]pyrimidina-3(1,2)- benzenacyclooctaphan-8-one339.5 37

(1³E,1⁴E)-5-methyl-1⁷- (methylamino)-4-oxa-2,7-diaza-1(5,3)-pyrazolo[1,5- a]pyrimidina-3(1,3)- benzenacyclooctaphan-8-one339.5 38

(1³E,1⁴E)-3⁵-hydroxy-1⁷- (methylamino)-2,7-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidina- 3(1,3)-benzenacyclooctaphan-8- one 339.3 39

(1³E,1⁴E)-3⁶-fluoro-34-methyl- 1⁷-(methylamino)-4-oxa-2,7-diaza-1(5,3)-pyrazolo[1,5- a]pyrimidina-3(1,3)-benzenacyclooctaphan-8-one 357.2 40

(1³E,1⁴E)-3⁵-methoxy-1⁷- (methylamino)-2,7-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidina- 3(1,3)-benzenacyclooctaphan-8- one 353.4 41

(1³E,1⁴E)-1⁷-(methylamino)-4- oxa-2,7-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidina- 3(3,5)-pyridinacyclooctaphan-8- one 326.6 42

(1³E,1⁴E)-1⁷-(methylamino)-2,6- diaza-1(5,3)-pyrazolo[1,5-a]pyrimidina-3(2,6)- pyridinacycloheptaphan-7-one 310.2 43

(1²Z,3³E,3⁴E)-3⁷-(methylamino)- 2,5-diaza-1(2,4)-thiazola-3(5,3)-pyrazolo[1,5- a]pyrimidinacyclooctaphan-4- one 330.2 44

(1³E,1⁴E)-1⁷-(methylamino)-2,7- diaza-1(5,3)-pyrazolo[1,5-a]pyrimidina-3(1,3)- benzenacyclooctaphane-4,8- dione 337.0 45

(1³E,1⁴E,3⁴E)-1⁷-(methylamino)- 31H-2,7-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidina- 3(4,1)-pyrazolacyclooctaphan-8- one 313.2 46

(1³E,1⁴E)-3⁵-fluoro-1⁷- (methylamino)-4-oxa-2,8-diaza-1(5,3)-pyrazolo[1,5- a]pyrimidina-3(1,2)- benzenacyclononaphan-9-one357.4 47

(1³E,1⁴E,3⁴E)-1⁷-(methylamino)- 31H-2,6-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidina- 3(4,1)-pyrazolacycloheptaphan- 7-one 299.2

Example 3: JAK/TYK2 Assay

10 mM test compound stock or 1 mM control compound stock (tofocitinib,ruxolitinib or staurosporine) in DMSO was diluted to 0.4 mM in DMSO. A3-fold series dilution was then performed in DMSO to generate 10different compound concentrations. The assay was carried out in 384-wellwhite plate. 0.5 uL of 40× compound DMSO solution at differentconcentrations was mixed with 10 uL. 2× enzyme prepared in reactionbuffer (20 mM HEPES, 10 mM MgCl₂, 0.01% Tween, 1 mM DTT, pH 7.5). 10 uL2× substrate mixture prepared in reaction buffer was then added to startthe reaction. A short spin was done to settle down all solutions to thebottom of the plate. Final concentrations of test compound in thereaction mixture were 10000, 3333, 1111, 370, 123, 41.2, 13.7, 4.57,1.52 and 0.51 nM. Concentrations of control compound were ten timesless. Enzymatic reaction was conducted at 25° C. for 1-2 hours. 10 uL ofKinase Glo Reagents was added to stop the reaction and generate theluminescent signal which was measured using Envision. Luminescencesignal was inversely related to kinase activity. Reaction mixture whichdoesn't contain enzyme served as negative control. The mixture withoutany compound was the positive control. Final concentration of enzymesand substrates and incubation time are summarized in the table below.

[enz] [ATP] [sub] time JAK1 7.5 nM 2 uM 30 uM (IRS-1) 1 hr JAK2 0.8 nM 2uM  4 uM (pEY) 1 hr JAK3 1.5 nM 2 uM  4 uM (pEY) 1 hr TYK2   9 nM 2 uM30 uM (IRS-1) 1 hr

Example 4: Co-Stimulation Assay in Lysed Whole Blood; JAK2: GM-CSFStimulated STAT5 Phosphorylation and JAK1/TYK2 Stimulated STAT1Phosphorylation Assay Human Blood Lysis Using Abcam's RBC Lysis Buffer

Dilute RBC lysis buffer to 1× in distilled water. Add 2 mL blood to 38mL of 1×RBC-lysis buffer. Incubate for 15 mins at RT, in dark. Spin at300 g, 5 mins, to collect the pellet. Re-lyse if necessary. Re-suspendpellet in 5 mL of cRPMI.

Compound and Cytokine Treatment

Aliquot 80 μL of lysed human blood in to wells of 96 deep-well plate.Add 10 μl of (10× conc.) of different concentrations of compounds to allwells except controls (unstained and unstimulated) and mix it with thehelp of 100 uL multichannel. Add 10 uL of RPMI media in controls. Fordilution of compounds and dilution range please refer Appendix. Incubateon water bath or CO₂ incubator for 1 hour at 37° C. Add 10 μl of (10×conc.) of cytokine mix (GM-CSF and IFNa) (final conc. 10 ng/mL of GM-CSFand 100 ng/mL of IFNa) to each well except unstimulated and unstainedcontrols and incubate further for 20 minutes on water bath at 37° C.

RBC Lysis and Fixation

Add 900 μL of prewarmed 1× Fix/Lyse solution (Appendix) and mix itproperly using 1000 μl multichannel, incubate further on water bath at37° C. for 10 minutes (which includes time of addition). Centrifuge at800×g for 5 minutes at 40° C.; remove 900 uL of supernatant and add 900L of 1×PBS. Centrifuge at 800×g for 5 minutes at 40° C., remove 900 μLof supernatant. Wash one more time with 900 μL of PBS (optional) andresuspend pellets in 100 uL of PBS.

Permeabilization

Disrupt the pellet by gentle tapping and resuspend in 1000 μL of BDPhosflow Perm Buffer III and incubate plate on ice for 30 minutes.Centrifuge plate at 800×g for 5 minutes at 40° C. Wash two more timeswith 1000 μL of BD Pharmingen Stain Buffer.

Antibody Treatment

Disrupt the pellet by gentle tapping. Resuspend pellets in 100 uL ofStain Buffer and add L of pSTAT5_AF488 Ab and 5 uL of pSTAT1_PE in allwells except unstained control and mix properly using 200 μlmultichannel, incubate overnight at 40° C. Add 900 μL of wash buffer andcentrifuge at 1800 rpm for 3 minutes at 40° C. Wash one more time with1000 μL of BD Pharmingen Stain Buffer. Finally resuspend the pellet in300 uL of BD Pharmingen Stain Buffer. Transfer the cells to 96-wellv-bottom plate and acquire the cells in Beckman Coulter CytExpert.Acquiring cells in Flow Cytometer: Keep the threshold value to 250 andcell concentration should not exceed 100-500 cells/μL. Acquire at least5,000-10,000 cells.

Appendix Preparation of Reagents

RPMI 1640 Complete Medium: RPMI 1640 media+10% FBS.

Cytokine dilution: 1) GM-CSF Stock at 100 ug/mL. Prepare an intermediatedilution of 1 ug/mL by adding 2 uL of stock into 198 uL of cRPMI.Further dilute to 100 ng/mL by adding 100 uL of the intermediate stockto 900 uL of cRPMI. 2) IFNa Stock at 200 ug/mL. Dilute IFNa stock 1:200by adding 5 uL of stock into the 1000 uL of 100 ng/mL GM-CSF workingstock as above to give a combined working stock of 1000 ng/mL of IFNaand 100 ng/mL GM-CSF (10×). Keep it on ice until used.

Lyse/Fix buffer preparation: Dilute 5× Lyse/Fix buffer to 1× using MQwater and keep at 37° C. until used.

BD Phosflow perm buffer III: Keep on ice/fridge.

Compound Dilution

Final 10× concentra- concentra- tion, tion, Sample nM nM Dilution 110,000 100,000  2 μL of 10 mM compound + 198 μL of cRPMI media 2 3333.333,333  60 μL of A + 120 μL of cRPMI media 3 1111.1 11,111  60 uL of B +120 μL of cRPMI media 4 370.4 3,704  60 μL of C + 120 μL of cRPMI media5 123.5 1,235  60 μL of D + 120 μL of cRPMI media 6 41.2 412  60 μL ofE + 120 μL of cRPMI media 7 13.7 137  60 μL of F + 120 μL of cRPMI media8 4.6 46  60 μL of G + 120 μL of cRPMI media 9 0 0  2 μL of DMSO + 198μL of cRPMI media

IC50 values are shown in the table below.

IFN-a/Jak1Tyk2 Compound IC50  7 A 12 B 13 A 14 A 15 A 16 A 17 A 18 B 19B 20 B 21 B 22 B 23 B 24 B 25 B 26 B 27 B 28 B 29 B 30 B 31 B 32 B 33 B34 B 35 B 36 B 37 C 38 C 39 C 40 C 41 C 42 C 43 C 44 C 45 C 46 C 47 C A:IC₅₀ ≤ 500 nM; B: IC₅₀ ≥ 100 nM and <1 uM; C: IC₅₀ ≥ 1 uM and ≤10 uM

The examples and embodiments described herein are for illustrativepurposes only and in some embodiments, various modifications or changesare to be included within the purview of disclosure and scope of theappended claims.

What is claimed is:
 1. A compound having the structure of Formula (I) orFormula (II):

wherein:

is C₃-C₆cycloalkyl, C₆-C₁₀aryl, C₂-C₉heterocycloalkyl, orC₂-C₉heteroaryl, wherein C₃-C₆cycloalkyl, C₆-C₁₀aryl,C₂-C₉heterocycloalkyl, or C₂-C₉heteroaryl is optionally substituted with1, 2, 3, or 4 R₇; X is —O—, —C(R₉)(R₁₀)—, —C(R₉)(R₁₀)—O—, —O—C(R₉)(R₁₀),—C(O)—, —C(O)N(R₃)—, —N(R₃)C(O)—, or —N(R₁₇)—; L₁ is —C(O)N(R₃)—,—N(R₃)C(O)—, —C(R₉)(R₁₀)—O—, or —O—C(R₉)(R₁₀)—; L₂ is —N(R₆)—,—N(R₆)CH₂—, or —CH₂N(R₆)—; each R₁ is independently selected fromhydrogen, deuterium, C₁-C₆alkyl, and C₁-C₆deuteroalkyl; each R₂ isindependently selected from hydrogen, deuterium, C₁-C₆alkyl, andC₁-C₆deuteroalkyl; or R₁ and R₂ are combined to form a 3-, 4-, 5-, or6-membered cycloalkyl ring or a 4-, 5-, or 6-membered heterocycloalkylring; each R₃ is independently hydrogen or C₁-C₆alkyl; or R₂ and R₃together with the atoms to which they are attached are combined to forma 5- or 6-membered heterocycloalkyl ring optionally substituted 1, 2, or3 with groups selected from halogen, —OH, C₁-C₆alkyl, and—C₁-C₆alkyl-OH; R₄ is selected from hydrogen, deuterium, C₁-C₆alkyl,C₁-C₆deuteroalkyl, C₁-C₆heteroalkyl, C₃-C₆cycloalkyl, andC₂-C₉heterocycloalkyl; R₅ is selected from hydrogen, deuterium,C₁-C₆alkyl, C₁-C₆deuteroalkyl, C₁-C₆heteroalkyl, C₃-C₆cycloalkyl, andC₂-C₉heterocycloalkyl; R₁₃ is hydrogen, deuterium, C₁-C₆alkyl, orC₁-C₆deuteroalkyl; or R₅ and R₁₃ together with the atoms to which theyare attached are combined to form a 5- or 6-membered heterocycloalkylring or a 5- or 6-membered heteroaryl ring, wherein the 5- or 6-memberedheterocycloalkyl ring or 5- or 6-membered heteroaryl ring is optionallysubstituted with 1, 2, or 3 groups selected from halogen, C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆alkoxy, and C₁-C₆haloalkoxy; R₆ is hydrogen orC₁-C₆alkyl; each R₇ is independently selected from deuterium, halogen,C₁-C₆alkyl, C₁-C₆deuteroalkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy,C₁-C₆heteroalkyl, oxo, —OR₁₁, —N(R₁₁)₂, —CN, —C(═O)R₁₂, —C(═O)OR₁₁,—C(═O)N(R₁₁)₂, —NR₁₁C(═O)R₁₂, —NR₁₁S(═O)₂R₁₂, —S(═O)₂R₁₂, and—S(═O)₂N(R₁₁)₂; each R₉ and each R₁₀ are independently selected fromhydrogen, deuterium, C₁-C₆alkyl, and C₁-C₆deuteroalkyl; each R₁ isindependently selected from hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆heteroalkyl, and phenyl, wherein phenyl is optionally substitutedwith 1, 2, or 3 groups selected from halogen, C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₂-C₉heterocycloalkyl,C₂-C₉heteroaryl, —OR₁₄, —N(R₁₄)₂, —C(═O)OR₁₄, and —C(═O)N(R₁₄)₂; eachR₁₂ is independently selected from C₁-C₆alkyl and C₁-C₆heteroalkyl; eachR₁₄ is independently selected from hydrogen, C₁-C₆alkyl, andC₁-C₆haloalkyl; R₁₇ is hydrogen or C₁-C₆alkyl; R₁₈ is hydrogen,deuterium, halogen, C₁-C₆alkyl, or C₁-C₆deuteroalkyl; and n is 1, 2, 3,or 4; or a pharmaceutically acceptable salt or solvate thereof.
 2. Thecompound of claim 1, or a pharmaceutically acceptable salt or solvatethereof, having the structure of Formula (I):


3. The compound of claim 1, or a pharmaceutically acceptable salt orsolvate thereof, having the structure of Formula (II):


4. The compound of any one of claims 1-3, or a pharmaceuticallyacceptable salt or solvate thereof, wherein

is C₆-C₁₀aryl optionally substituted with 1, 2, or 3 R₇.
 5. The compoundof claim 4, or a pharmaceutically acceptable salt or solvate thereof,wherein

is phenyl optionally substituted with 1, 2, or 3 R₇.
 6. The compound ofany one of claims 1-3, or a pharmaceutically acceptable salt or solvatethereof, wherein

is C₂-C₉heteroaryl optionally substituted with 1, 2, or 3 R₇.
 7. Thecompound of claim 6, or a pharmaceutically acceptable salt or solvatethereof, wherein

is C₂-C₉heteroaryl selected from oxazolyl, thiazolyl, pyrazolyl,furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, isoxazolyl,isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl,wherein oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl,imidazolyl, triazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl,pyrazinyl, and pyridazinyl are optionally substituted with 1, 2, or 3R₇.
 8. The compound of any one of claims 1-7, or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₇ is selected from halogen,C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, and —CN.
 9. The compound ofclaim 7, or a pharmaceutically acceptable salt or solvate thereof,wherein

is C₂-C₉heteroaryl selected from:


10. The compound of any one of claims 1-3, or a pharmaceuticallyacceptable salt or solvate thereof, wherein

is C₂-C₉heterocycloalkyl optionally substituted with 1, 2, or 3 R₇. 11.The compound of any one of claims 1-3, or a pharmaceutically acceptablesalt or solvate thereof, wherein

is C₃-C₆cycloalkyl optionally substituted with 1, 2, 3, or 4 R₇.
 12. Thecompound of claim 10 or claim 11, or a pharmaceutically acceptable saltor solvate thereof, wherein R₇ is selected from halogen, C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆alkoxy, and oxo.
 13. The compound of claim 10, or apharmaceutically acceptable salt or solvate thereof, wherein

is C₂-C₉heterocycloalkyl selected from.


14. The compound of any one of claims 1-13, or a pharmaceuticallyacceptable salt or solvate thereof, wherein L₁ is —C(O)N(R₃)—.
 15. Thecompound of any one of claims 1-13, or a pharmaceutically acceptablesalt or solvate thereof, wherein L₂ is —N(R₆).
 16. A compound having thestructure of Formula (III) or Formula (IV):

wherein: X is —O— or —C(R₉)(R₁₀)—; Y is ═N— or ═C(R₁₅)—; Z is ═N— or═C(R₁₆)—; each R₁ is independently selected from hydrogen, deuterium,C₁-C₆alkyl, and C₁-C₆deuteroalkyl; each R₂ is independently selectedfrom hydrogen, deuterium, C₁-C₆alkyl, and C₁-C₆deuteroalkyl; R₃ ishydrogen or C₁-C₆alkyl; R₄ is selected from hydrogen, deuterium,C₁-C₆alkyl, C₁-C₆deuteroalkyl, C₁-C₆heteroalkyl, C₃-C₆cycloalkyl, andC₂-C₉heterocycloalkyl; R₅ is selected from hydrogen, deuterium,C₁-C₆alkyl, C₁-C₆deuteroalkyl, C₁-C₆heteroalkyl, C₃-C₆cycloalkyl, andC₂-C₉heterocycloalkyl; R₁₃ is hydrogen, deuterium, C₁-C₆alkyl, orC₁-C₆deuteroalkyl; or R₅ and R₁₃ together with the atoms to which theyare attached are combined to form a 5- or 6-membered heterocycloalkylring or a 5- or 6-membered heteroaryl ring, wherein the 5- or 6-memberedheterocycloalkyl ring or 5- or 6-membered heteroaryl ring is optionallysubstituted with 1, 2, or 3 groups selected from halogen, C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆alkoxy, and C₁-C₆haloalkoxy; R₆ is hydrogen orC₁-C₆alkyl; R₇ and R₈ are independently selected from hydrogen,deuterium, halogen, C₁-C₆alkyl, C₁-C₆deuteroalkyl, —C₁-C₆alkyl-OH,C₁-C₆haloalkyl, C₁-C₆alkoxy, C₃-C₆cycloalkyl, C₂-C₉heterocycloalkyl,C₂-C₉heteroaryl, C₆-C₁₀aryl, —OR₁₁, —N(R₁₁)₂, —CN, —C(═O)R₁₂,—C(═O)OR₁₁, —C(═O)N(R₁₁)₂, —NR₁₁C(═O)R₁₁, —NR₁₁S(═O)₂R₁₁, —S(═O)₂R₁₁,and —S(═O)₂N(R₁₁)₂, wherein C₃-C₆cycloalkyl, C₂-C₉heterocycloalkyl,C₂-C₉heteroaryl, or C₆-C₁₀aryl are optionally substituted with 1, 2, or3 groups selected from halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy,and C₁-C₆haloalkoxy; R₉ and R₁₀ are independently selected fromhydrogen, deuterium, C₁-C₆alkyl, and C₁-C₆deuteroalkyl; each R₁₁ isindependently selected from hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆heteroalkyl, and phenyl, wherein phenyl is optionally substitutedwith 1, 2, or 3 groups selected from halogen, C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₂-C₉heterocycloalkyl,C₂-C₉heteroaryl, —OR₁₄, —N(R₁₄)₂, —C(═O)OR₁₄, and —C(═O)N(R₁₄)₂; eachR₁₁ is independently selected from C₁-C₆alkyl and C₁-C₆heteroalkyl; eachR₁₄ is independently selected from hydrogen, C₁-C₆alkyl, andC₁-C₆haloalkyl; R₁₅ and R₁₆ are independently selected from hydrogen,deuterium, halogen, C₁-C₆alkyl, C₁-C₆deuteroalkyl, C₁-C₆haloalkyl,C₁-C₆alkoxy, C₁-C₆heteroalkyl, —OR₁₁, —N(R₁₁)₂, —CN, —C(═O)R₁₁,—C(═O)OR₁₁, —C(═O)N(R₁₁)₂, —NR₁₁C(═O)R₁₂, —NR₁₁S(═O)₂R₁₂, —S(═O)₂R₁₁,and —S(═O)₂N(R₁₁)₂; R₁₈ is hydrogen, deuterium, halogen, C₁-C₆alkyl, orC₁-C₆deuteroalkyl; and n is 1, 2, 3, or 4; or a pharmaceuticallyacceptable salt or solvate thereof.
 17. The compound of claim 16, or apharmaceutically acceptable salt or solvate thereof, having thestructure of Formula (III):


18. The compound of claim 16, or a pharmaceutically acceptable salt orsolvate thereof, having the structure of Formula (IV):


19. The compound of any one of claims 16-18, or a pharmaceuticallyacceptable salt or solvate thereof, wherein Y is ═C(R₁₅)— and Z is═C(R₁₆)—.
 20. The compound of any one of claims 16-18, or apharmaceutically acceptable salt or solvate thereof, wherein Y is ═N—and Z is ═C(R₁₆)—.
 21. The compound of any one of claims 16-20, or apharmaceutically acceptable salt or solvate thereof, wherein R₁₆ isselected from hydrogen, halogen, C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆alkoxy, and —CN.
 22. The compound of any one of claims 16-21, or apharmaceutically acceptable salt or solvate thereof, wherein R₁₆ isselected from hydrogen, halogen, or C₁-C₆alkyl.
 23. The compound of anyone of claims 16-18, or a pharmaceutically acceptable salt or solvatethereof, wherein Y is ═C(R₁₅)— and Z is ═N—.
 24. The compound of any oneof claims 16-23, or a pharmaceutically acceptable salt or solvatethereof, wherein R₁₅ is selected from hydrogen, halogen, C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆alkoxy, and —CN.
 25. The compound of any one ofclaims 16-24, or a pharmaceutically acceptable salt or solvate thereof,wherein R₁₅ is selected from hydrogen, halogen, or C₁-C₆alkyl.
 26. Thecompound of any one of claims 16-18, or a pharmaceutically acceptablesalt or solvate thereof, wherein Y is ═N— and Z is ═N—.
 27. The compoundof any one of claims 16-26, or a pharmaceutically acceptable salt orsolvate thereof, wherein R₇ and R₈ are independently selected fromhydrogen, halogen, C₁-C₆alkyl, —C₁-C₆haloalkyl, C₁-C₆alkoxy,C₂-C₉heteroaryl, —OR₁₁, —N(R₁₁)₂, —CN, —C(═O)OR₁₁, —C(═O)N(R₁₁)₂,—NR₁₁C(═O)R₁₂, —NR₁₁S(═O)₂R₁₂, —S(═O)₂R₁₂, and —S(═O)₂N(R₁₁)₂, whereinC₂-C₉heteroaryl is optionally substituted with 1, 2, or 3 groupsselected from halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, andC₁-C₆haloalkoxy.
 28. The compound of any one of claims 16-27, or apharmaceutically acceptable salt or solvate thereof, wherein R₇ and R₈are independently selected from hydrogen, halogen, C₁-C₆alkyl,—C₁-C₆haloalkyl, C₂-C₉heteroaryl, —OR₁₁, —CN, —C(═O)N(R₁₁)₂, and—NR₁₁S(═O)₂R₁₂, wherein C₂-C₉heteroaryl is optionally substituted with 1or 2 groups selected from halogen or C₁-C₆alkyl.
 29. The compound of anyone of claims 16-28, or a pharmaceutically acceptable salt or solvatethereof, wherein R₇ and R₈ are independently selected from hydrogen,halogen, and C₁-C₆alkyl.
 30. The compound of any one of claims 1-29, ora pharmaceutically acceptable salt or solvate thereof, wherein X is —O—.31. The compound of any one of claims 1-29, or a pharmaceuticallyacceptable salt or solvate thereof, wherein X is —C(R₉)(R₁₀)—.
 32. Thecompound of claim 31, or a pharmaceutically acceptable salt or solvatethereof, wherein R₉ and R₁₀ are hydrogen.
 33. The compound of any one ofclaims 1-32, or a pharmaceutically acceptable salt or solvate thereof,wherein R₄ and R₅ are independently selected from hydrogen andC₁-C₆alkyl.
 34. The compound of any one of claims 1-33, or apharmaceutically acceptable salt or solvate thereof, wherein R₄ ishydrogen and R₅ is C₁-C₆alkyl.
 35. The compound of any one of claims1-34, or a pharmaceutically acceptable salt or solvate thereof, whereinR₃ is hydrogen.
 36. The compound of any one of claims 1-35, or apharmaceutically acceptable salt or solvate thereof, wherein R₆ ishydrogen.
 37. The compound of any one of claims 1-36, or apharmaceutically acceptable salt or solvate thereof, wherein n is
 1. 38.The compound of any one of claims 1-36, or a pharmaceutically acceptablesalt or solvate thereof, wherein n is
 2. 39. The compound of any one ofclaims 1-36, or a pharmaceutically acceptable salt or solvate thereof,wherein n is
 3. 40. The compound of any one of claims 1-39, or apharmaceutically acceptable salt or solvate thereof, wherein each R₁ ishydrogen.
 41. The compound of any one of claims 1-40, or apharmaceutically acceptable salt or solvate thereof, wherein each R₂ ishydrogen.
 42. The compound of any one of claims 1-41, or apharmaceutically acceptable salt or solvate thereof, wherein R₁₈ ishydrogen.
 43. A compound selected from:

or a pharmaceutically acceptable salt or solvate thereof.
 44. A compoundselected from:

pharmaceutically acceptable salt or solvate thereof.
 45. A compoundselected from:

or a pharmaceutically acceptable salt or solvate thereof.
 46. A compoundselected from:

or a pharmaceutically acceptable salt or solvate thereof.
 47. A compoundselected from:

or a pharmaceutically acceptable salt or solvate thereof.
 48. Apharmaceutical composition comprising a compound of any one of claims1-47, or a pharmaceutically acceptable salt or solvate thereof, and apharmaceutically acceptable excipient.
 49. A method of treating aninflammatory or autoimmune disease in a patient in need thereof,comprising administering to the patient a therapeutically effectiveamount of a compound of any one of claims 1-47, or a pharmaceuticallyacceptable salt or solvate thereof.
 50. The method of claim 49, whereinthe disease is selected from rheumatoid arthritis, multiple sclerosis,psoriasis, lupus, intestinal bowel disease, Crohn's disease, ulcerativecolitis, ankylosing spondylitis, vitiligo, and atopic dermatitis.